abacavir and HIV-Infections

There are more than 30 agents available for the treatment of HIV with guidelines shifting toward integrase strand transfer inhibitors (INSTIs) as part of first line therapy. The fixed dose combination of dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) is a convenient, well tolerated, and highly effective option for treating HIV infection and remains a first line therapy across several prominent guidelines.. In this drug evaluation, the authors provide a comprehensive overview of DTG/ABC/3TC for the treatment of HIV including the pharmacokinetics, pharmacodynamics, efficacy, safety, and tolerability. The authors also provide the reader with their expert perspectives on this particular treatment strategy.. While DTG/ABC/3TC remains a valuable HIV treatment option, newer combination regimens have entered the market. Bictegravir with tenofovir alafenamide and emtricitabine offers the benefit of same day initiation and efficacy in hepatitis B co-infection, while new two-drug regimens enhance the simplicity of HIV treatment. Continued study is required into the mechanisms and optimal management strategies for weight gain for many regimens, including DTG/ABC/3TC.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations.. In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230).. Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I. Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV.. WHO.

Topics: Adolescent; Adult; Anti-HIV Agents; Child; Cross-Sectional Studies; Cyclopropanes; Dideoxyadenosine; HIV Infections; Humans; Infant; Nucleosides; Observational Studies as Topic; Prospective Studies; Retrospective Studies; Reverse Transcriptase Inhibitors

Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation.. A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling.. Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation.. In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; HIV Infections; Humans; Infant, Newborn; Lopinavir; Malnutrition; Ritonavir

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.

Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Atovaquone; CD4 Lymphocyte Count; CD4-CD8 Ratio; COVID-19; Dideoxynucleosides; Female; Glucocorticoids; Graft Rejection; HIV Infections; HIV-1; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Male; Middle Aged; Mycophenolic Acid; Pneumonia, Pneumocystis; Prednisolone; Raltegravir Potassium; RNA, Viral; SARS-CoV-2; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Highly active antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20-30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which antiretroviral drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients' neurocognition and quality of life.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Astrocytes; Atazanavir Sulfate; Benzoxazines; Central Nervous System; Cognitive Dysfunction; Cyclopropanes; Dideoxynucleosides; Endothelial Cells; HIV Infections; Humans; Neurons; Nevirapine; Nitriles; Oligodendroglia; Pyrimidines

Human leukocyte antigen (HLA)-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4-8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and spontaneous reporting data.. A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016.. Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE).. Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Mass Screening

Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS.. Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight.. IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

Topics: Allergens; Anti-Infective Agents; Anti-Retroviral Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Immunization

Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients.. We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect.. The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy.. The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA Antigens; Humans; Male; Nevirapine; Odds Ratio; Polymorphism, Single Nucleotide

Abacavir's potential to cause cardiovascular disease (CVD) among people living with HIV (PLWH) is debated. We conduct a systematic review and meta-analyses to assess CVD risk from recent and cumulative abacavir exposure.. We searched Medline, Embase, Web of Science, abstracts from Conference on Retroviruses and Opportunistic Infections, and International AIDS Society/AIDS Conferences and bibliographies of review articles to identify research studies published through 2018 on CVD risk associated with abacavir exposure among PLWH. Studies assessing risk of CVD associated with recent (exposure within last 6 months) or cumulative abacavir exposure across all age-groups were eligible. Risks were quantified using fixed- and random-effects models.. Of 378 unique citations, 68 full-text research articles and abstracts were reviewed. Seventeen studies assessed risk of CVD from recent or cumulative abacavir exposure. Summary relative risk (sRR) is increased for recent exposure (n=16 studies, sRR=1.61; 95% confidence interval: 1.48-1.75), higher in antiretroviral-therapy-naive population (n=5, 1.91; 1.48-2.46) and all studies reported RR>1. The sRR for recent exposure was similarly increased for the outcome of acute myocardial infarction, and for studies that adjusted for substance abuse, smoking, prior CVD, traditional CVD risk factors, and CD4 cell-count/HIV viral load. The sRR was increased for cumulative abacavir exposure (per year) (n=4, 1.12; 1.05-1.20) but no increase was seen after adjusting for recent exposure (n=5, 1.00; 0.93-1.08).. Our findings suggest an increased risk of CVD from recent abacavir exposure. The risk remained elevated after adjusting for potential confounders. Further investigations are needed to understand CVD risk from cumulative exposure.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Risk Assessment; Young Adult

: There is a long-lasting controversy surrounding an association between abacavir (ABC) and an increased risk of cardiovascular disease in HIV-positive patients. Although differing in their specifics, a number of published cohort studies and clinical trials support such an association, usually relating it to recent exposure to the drug, independently of traditional predisposing factors. However, other clinical trials have failed to reveal such a relation and have pointed to methodological differences to explain discrepancies. Significantly, the controversy has been fueled by the lack of a credible mechanism of action to justify the putative detrimental actions of ABC. There is a myriad of contradictory clinical indicators which are not clearly compatible with known profiles of either vascular physiopathology or pharmacological interference. However, basic research has recently hinted at altered homeostatic mechanisms, though this requires clinical validation. In particular, recurrent evidence - both clinical and experimental - relates ABC with vascular inflammation, a leading contributor to the atherosclerotic plaque and thrombosis. ABC's chemical structure is very close to that of endogenous purines (ATP, ADP and AMP), major paracrine signaling molecules capable of triggering prothrombotic and proinflammatory vascular programs. Other proposed mechanisms are a competitive inhibition of guanylyl cyclase in platelets and a subsequent decrease in cyclic guanosine monophosphate (cGMP). The present review aims to shed light on this complex subject by summarizing and critically evaluating all the available clinical data regarding a relationship between ABC and cardiovascular disease, and to put forward potential pharmacological explanations compatible with both the clinical scenario and experimental findings.

Topics: Anti-HIV Agents; Atherosclerosis; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans; Vasculitis

Concerns exist about the toxicity of drugs used in the implementation of large-scale antiretroviral programmes, and documentation of antiretroviral toxicity is essential. We did a systematic review and meta-analysis of adverse events among children and adolescents receiving regimens that contain abacavir, a widely used antiretroviral drug.. We searched bibliographic databases and abstracts from relevant conferences from Jan 1, 2000, to March 1, 2015. All experimental and observational studies of HIV-infected patients aged 0-18 years who used abacavir, were eligible. Incidence of adverse outcomes in patients taking abacavir (number of new events in a period divided by population at risk at the beginning of the study) and relative risks (RR) compared with non-abacavir regimens were pooled with random effects models.. Of 337 records and 21 conference abstracts identified, nine studies (eight full-text articles and one abstract) collected information about 2546 children, of whom 1769 (69%) were on abacavir regimens. Among children and adolescents taking abacavir, hypersensitivity reactions (eight studies) had a pooled incidence of 2·2% (95% CI 0·4-5·2); treatment switching or discontinuation (seven studies) pooled incidence was 10·9% (2·1-24·3); of grade 3-4 adverse events (six studies) pooled incidence was 9·9% (2·4-20·9); and adverse events other than hypersensitivity reaction (six studies) pooled incidence was 21·5% (2·8-48·4). Between-study inconsistency was significant for all outcomes (p<0·0001 for all inconsistencies). Incidence of death (four studies) was 3·3% (95% CI 1·5-5·6). In the three randomised clinical trials with comparative data, no increased risk of hypersensitivity reaction (pooled RR 1·08; 95% CI 0·19-6·15), grade 3 or 4 events (0·79 [0·44-1·42]), or death (1·72 [0·77-3·82]) was noted for abacavir relative to non-abacavir regimens. None of the reported deaths were related to abacavir.. Abacavir-related toxicity occurs early after ART initiation and is manageable. Abacavir can be safely used for first-line or second-line antiretroviral regimens in children and adolescents, especially in sub-Saharan Africa were HLA B5701 genotype is rare.. WHO.

Topics: Adolescent; Anti-HIV Agents; Child; Child Health Services; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Observational Studies as Topic; Practice Guidelines as Topic

The advent of combination antiretroviral drug regimens has transformed HIV infection from a fatal illness into a manageable chronic condition. All patients with HIV infection should be considered for antiretroviral therapy, regardless of CD4 count or HIV viral load, for individual benefit and to prevent HIV transmission. Antiretroviral drugs affect HIV in several ways: entry inhibitors block HIV entry into CD4 T cells; nucleotide and nucleoside reverse transcriptase inhibitors prevent reverse transcription from RNA to DNA via chain-terminating proteins; nonnucleoside reverse transcriptase inhibitors prevent reverse transcription through enzymatic inhibition; integrase strand transfer inhibitors block integration of viral DNA into cellular DNA; protease inhibitors block maturation and production of the virus. Current guidelines recommend six combination regimens for initial therapy. Five are based on tenofovir and emtricitabine; the other uses abacavir and lamivudine. Five include integrase strand transfer inhibitors. HIV specialists should assist with treating patients with complicated HIV infection, including patients with treatment-resistant HIV infection, coinfection with hepatitis B or C virus, pregnancy, childhood infections, severe opportunistic infections, complex drug interactions, significant drug toxicity, or comorbidities. Family physicians can treat most patients with HIV infection effectively by choosing appropriate treatment regimens, monitoring patients closely, and retaining patients in care.

Topics: Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Emtricitabine; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Tenofovir

Most HIV-infected subjects will receive a treatment regimen including abacavir or tenofovir. Therefore, clarifying if there is an increased risk of acute myocardial infarction (AMI) among those exposed to abacavir is of the utmost importance. Due to the low frequency of AMI in this young population (2-5 per 1000 patients/year), efforts to clarify this have been quite controversial. While some observational cohorts have found a statistically significant association, others have not. Meta-analysis of randomized clinical trials offering the highest scientific evidence found no association at all, but with a limited statistical power to definitely rule out a small effect. A channelling or selection bias has been demonstrated in cohort studies, favouring the prescription of abacavir to subjects with or at risk for chronic kidney disease, and therefore, with an intrinsic increased cardiovascular risk. The recent NA-ACCORD cohort study does not identify an increased risk for AMI associated with recent abacavir use in a fully adjusted model (HR 1.33; 95%CI:0.96, 1.88). However, it does find an association in a second analysis restricted to treatment-naïve persons, with higher differences in baseline characteristics among compared arms. A critical review of the compiled available evidence is therefore mandatory, particularly in light of the first single-tablet regimen to receive approval that does contain abacavir.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Clinical Trials as Topic; Dideoxynucleosides; HIV Infections; Humans; Meta-Analysis as Topic; Myocardial Infarction; Risk

Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients.. In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies.. Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration. In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tablets

Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols.. Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202.. Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5 × 10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition.. No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Genome-Wide Association Study; HIV Infections; HIV-1; Humans; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Animals; Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Medication Adherence; Mutation; Oxazines; Piperazines; Practice Guidelines as Topic; Pyridones; Reverse Transcriptase Inhibitors; Tablets

With the introduction of the coformulated dolutegravir, abacavir and lamivudine , a new single tablet regimen (STR) is made available for the use in treatment-naive and treatment-experienced HIV-infected patients. This drug combination is the fourth STR that will be positioned next to the STRs with efavirenz, rilpivirine or elvitegravir as third agents, respectively.. The objective of this review is to provide an overview of the efficacy and safety of the combined dolutegravir/abacavir/lamivudine coformulation. The review will focus on dolutegravir and includes both published data as well as data presented at recent major international HIV/AIDS conferences.. The dolutegravir/abacavir/lamivudine regimen is highly effective in achieving sustained suppression of HIV-1 RNA plasma concentrations. The STR has a favorable safety profile and a low potential for drug interactions, which will contribute to a prominent role in therapy. As this STR contains abacavir as backbone component, the use requires patients to be HLA-B*5701 negative, with good hepatic function. Other first-line treatment combinations are preferred for patients with hepatitis B co-infection or with a high cardiovascular risk.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Interactions; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; RNA, Viral; Tablets

Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions.

Topics: Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Heterogeneity; HIV Infections; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; T-Lymphocytes

Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases. We searched four electronic databases, four conference proceedings and two clinical trial registries in August 2014, without language restrictions. Experimental and observational studies with control groups that examined the efficacy and safety of abacavir-containing regimens in comparison with other NRTIs as first-line treatment for HIV-infected children and adolescents aged between one month and eighteen years were eligible. Two authors independently screened search results, extracted data and assessed the risk of bias of included studies using a pre-specified, standardised data extraction form and validated risk of bias tools. We also assessed the quality of evidence per outcome with the GRADE tool.. We included two randomised controlled trials (RCTs) and two analytical cohort studies with a total of 10,595 participants. Among the RCTs we detected no difference in virologic suppression after a mean duration of 48 weeks between abacavir- and stavudine-containing regimens (2 trials; n = 326: RR 1.28; 95 % CI 0.67-2.42) with significant heterogeneity (P = 0.02; I(2) = 81 %). We also found no significant differences between the two groups for adverse events and death. After five years of follow-up, virologic suppression improved with abacavir (1 trial; n = 69: RR 1.96; 95 % CI 1.11-3.44). For cohort studies, we detected that the virologic suppression activity of abacavir was less effective than stavudine in both the lopinavir/ritonavir (1 study, n = 2165: RR 0.79, 95 % CI 0.67-0.92) and efavirenz sub-groups (1 study, n = 3204: RR 0.79, 95 % CI 0.67-0.92) respectively. The quality of evidence from RCTs was moderate for virologic suppression but low for death and adverse events, while that of cohort studies was low for all three these outcomes.. Available evidence showed little or no difference between abacavir-containing regimen and other NRTIs regarding efficacy and safety when given to children and adolescents as a first-line antiretroviral therapy.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lopinavir; Male; Ritonavir; Stavudine

Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients.. This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014.. The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.

Topics: Animals; Dideoxynucleosides; Drug Combinations; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Currently, the treatment of human immunodeficiency virus involves combination therapy, as antiretroviral therapy(ART). The treatment has improved steadily since the advent of potent combination therapy in 1996. New drugs that offer new mechanisms of action, improvements in potency and activity even against multidrug-resistant viruses, dosing convenience, and tolerability have been approved. Among ART with useful drugs, there are two important examinations before starting the treatment using the two kinds of drug. CCR5 co-receptor antagonists, maraviroc, prevent HIV entry into target cells by binding to CCR5 receptors. Genotypic assays have been developed that can determine or predict the co-receptor tropism(i.e., CCR5, CXCR4, or both) of the patient's dominant virus population. The assay for HIV-1 co-receptor usage should be performed whenever the use of a CCR5 antagonist is being considered. One of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), abacavir, is an important agent to develop recommended regimens for antiretroviral therapy. Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir-containing products, ZIAGEN, Epzicom, and Triumeq. Patients who carry the HLA-B*5701 allele are at high-risk of a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, performing a screening test for the HLA-B*5701 allele is recommended. [Review].

Topics: Alleles; Anti-Retroviral Agents; CCR5 Receptor Antagonists; Cyclohexanes; Dideoxynucleosides; HIV Infections; HIV-1; HLA-B Antigens; Humans; Maraviroc; Pharmacogenetics; Precision Medicine; Reverse Transcriptase Inhibitors; Triazoles; Viral Tropism

Antiretroviral therapy has evolved dramatically and more potent, safer and convenient drugs have replaced former compounds. Dolutegravir (DTG) is the most recently approved integrase inhibitor. It displays attractive properties such as one pill once daily (QD) dosing, high barrier to resistance and clean safety profile. Moreover, it is planned to be marketed, co-formulated with abacavir (ABC) and lamivudine (3TC) as a single-tablet regimen (STR). The availability of this QD single pill represents a significant step further for a large number of HIV-infected persons.. Updated summary of evidence-based information on efficacy and safety of DTG along with ABC and 3TC. All information available on antiretrovirals in the most advanced stages of clinical development reported in peer-reviewed journals or at international meetings has been reviewed.. The combination of DTG, ABC and 3TC displays a high efficacy, superior to many other antiretroviral combinations, including other convenient STR. The good safety profile, low potential for drug interactions and high resistance barrier of DTG- ABC-3TC are unique features than make this co-formulation the preferred choice as HIV therapy in multiple clinical scenarios, including most treatment-naïve and treatment-experienced patients, as part of switch strategies, and in patients with underlying serious medical conditions such as kidney abnormalities, liver disease, metabolic disturbances or neuropsychiatric conditions.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies.. A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model.. Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity.. This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics

The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence.. Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies.. We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (<100,000 or >100,000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression.. Meta-analytical pooling of RCTs with a direct comparison of abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL <50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94-1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99-1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90-1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99-1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant.. Our cumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Emtricitabine; HIV Infections; Humans; Lamivudine; Organophosphonates; Randomized Controlled Trials as Topic; Tenofovir; Treatment Outcome

UNAIDS estimates that 34 million people are currently living with the human immunodeficiency virus (HIV) worldwide. Currently recommended regimens for initiating HIV treatment consist of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir-boosted protease inhibitor (PI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs). However, there may be some patients for whom NNRTIs and PIs may not be appropriate. This is an update of the review published in the Cochrane Library Issue 3, 2009.. To evaluate the effects of any fixed-dose combination of three NRTIs (co-formulated abacavir-lamivudine-zidovudine) for initial treatment of HIV infection.. Between December 2010 and July 2011, we used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language or publication status.. We selected randomised controlled trials (RCTs) with a minimum follow-up time of six months which compared co-formulated abacavir-lamivudine-zidovudine with either PI-based or NNRTI-based therapy among antiretroviral-naive HIV-infected patients aged at least 13 years.. Three authors independently selected eligible studies, assessed risk of bias, and extracted data; resolving discrepancies by consensus. We calculated the risk ratio (RR) or mean difference (MD), as appropriate, with its 95% confidence interval (CI) and conducted meta-analysis using the random-effects method because of significant statistical heterogeneity (P<0.1).. We identified 15 potentially eligible RCTs, four of which met our inclusion criteria. The four included RCTs were conducted in the United States of America (USA); USA, Puerto Rico, Guatemala, Dominican Republic, and Panama; USA and Mexico; and Botswana, respectively. The RCTs compared co-formulated abacavir-lamivudine-zidovudine to treatment based on efavirenz (NNRTI), nelfinavir (PI), atazanavir (PI), and co-formulated lopinavir-ritonavir (PI), respectively. Overall, there was no significant difference in virological suppression between co-formulated abacavir-lamivudine-zidovudine and NNRTI- or PI-based therapy (4 trials; 2247 participants: RR 0.73, 95% CI 0.39 to 1.36). However, the results showed significant heterogeneity (I(2)=79%); with co-formulated abacavir-lamivudine-zidovudine inferior to NNRTI (1 trial, 1147 participants: RR 0.35, 95%CI 0.26 to 0.49) but with a trend towards co-formulated abacavir-lamivudine-zidovudine being superior to PI (3 trials, 1110 participants: RR 1.07, 95%CI 1.00 to 1.16; I(2)=0%). We found no significant differences between co-formulated abacavir-lamivudine-zidovudine and either PI or NNRTI on CD4+ cell counts (3 trials, 1687 participants: MD -0.01, 95%CI -0.11 to 0.09; I(2)=0%), severe adverse events (4 trials: RR 1.22, 95%CI 0.78 to 1.92; I(2)=62%) and hypersensitivity reactions (4 trials: RR 4.04, 95% CI 0.41 to 40.02; I(2)=72%). Only two studies involving PIs reported data on the lipid profile. One study found that the mean increase in total cholesterol from baseline to 96 weeks was significantly lower with co-formulated abacavir-lamivudine-zidovudine than with nelfinavir, but there were no differences with triglyceride levels. The second study found the fasting lipid profile to be comparable in both co-formulated abacavir-lamivudine-zidovudine and atazanavir arms at 48 weeks.The significant heterogeneity of effects for most outcomes evaluated was largely due to differences in the control therapy used in the included trials (i.e. NNRTIs or PIs). Using the GRADE approach, we rated the overall quality of the evidence on the relative effects of co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection as moderate. The main reason for downgrading the quality of the evidence was imprecision of the findings. The estimate of the treatment effect for each outcome has wide confidence intervals, which extend from the fixed-dose NRTI combination regimen being appreciably better to the regimen being a. This review provides evidence that co-formulated abacavir-lamivudine-zidovudine remains a viable option for initiating antiretroviral therapy, especially in HIV-infected patients with pre-existing hyperlipidaemia. The varied geographical locations of the included trials augment the external validity of these findings. We are moderately confident in our estimate of the treatment effects of the triple NRTI regimen as initial therapy for HIV infection. In the context of the GRADE approach, such moderate quality of evidence implies that the true effects of the regimen are likely to be close to the estimate of effects found in this review; but there is a possibility that they could be substantially different.  Further research should be geared towards defining the subgroup of HIV patients for whom this regimen will be most beneficial.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Nelfinavir; Oligopeptides; Pyridines; Randomized Controlled Trials as Topic; Zidovudine

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors; Standard of Care

Regimen simplification can be defined as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy may be considered candidates for a simplification strategy and, among them, those who have achieved virologic suppression. Several clinical trials have evaluated the efficacy of triple nucleoside combination as a simplification therapy in patients who achieved virologic suppression. The aim of this review is to combine randomised, controlled trials to examine whether in patients with undetectable viraemia on a Protease inhibitor (PI) based regimen simplification treatment with abacavir (ABC)-based triple-nucleoside combinations has similar rates of efficacy and tolerability compared with a PI regimen or simplification with a NNRTIs (efavirenz-EFV- or nevirapine-NVP) containing regimen. Studies were included if they had at least two of the three interventions, including one 3NRTI arm.. Electronic databases and conference proceedings were searched (1996-2012) with relevant search terms without limits to language.. Randomised controlled trials (RCTs) only are included in this review. Patients population is represented by HIV-infected adult patients treated with a PI-containing regimen (PI or boosted PI),  with undetectable viral load. Patients on a PI-containing regimen had three possibilities: continue the PI regimen or switch to a simplification maintenance regimen, including switch to a NNRTI (EFV or NVP) containing regimen, or switch to a triple-NRTI regimen (ABC-zidovudine-lamivudine). The primary outcomes were: proportion of patients discontinuing or switching antiretroviral therapy due to virologic failure or to adverse events; death (all cause) and AIDS defining illness; occurrence of myocardial infarction and cardiovascular disease. Secondary outcomes  were: proportion of patients maintaining an undetectable viral load (e.g. HIV-RNA <50 or <400 copies/mm(3)); change in mean CD4+ cell count; occurrence of lipodystrophy. We applied Cochrane Collaboration tools to assess each individual study for risk for bias.. We included eight RCT, for a total of 1,610 patients. All the studies included HIV-1 infected patients virologically suppressed after a successful treatment with PI containing ART. Articles included in the analysis were published between 2001 and 2010, and could be classified as low risk of bias trials in most of the domains considered. Overall, there was no significant difference between the participants on triple nucleoside combination and controls, either PI-based or NNRTI based in terms of overall failures, death and AIDS related events, and rates of patients with viral load below the detectability cut-off. For the outcomes discontinuation for adverse events and virologic failures, the RRs were not significant , albeit  being not far from the alpha level of 0.05, thus suggesting a weak evidence of lower incidence of side effects  and an higher incidence of virologic failure in the 3NRTI group compared to controls . Change in lipids and in CD4 cells from baselines were reported in 7 studies, but inconsistency in reporting these data did not allow quantitative analysis. However, all agreed that simplification with ABC had a favourable and significant impact on lipid metabolism compared to control group. An increase in CD4 cells count from baseline was evident in all analysed studies, without significant differences between ABC and controls in individual studies.. The strategy of switching to triple nucleoside regimens shows weak evidence of lower incidence of side effects and a higher incidence of virologic failure in the 3NRTI group compared to controls. Simplification with 3NRTI holds the advantages of preserving other classes of antiretroviral drugs, to lower blood lipids, and to be cost effective and simple to administer.Thus, simplification with triple nucleoside regimens AZT + 3TC + ABC should be still considered for individuals who are unable to tolerate or have contraindications to NNRTI or PI based regimens. Additional data are needed on longer-term efficacy of triple NRTI regimens, particularly on the development of antiretroviral resistance. Though studies in the current review were conducted between 2001 and 2010, the large majority of patients from studies analysed received old PI regimens (e.g., indinavir, ritonavir, nelfinavir, saquinavir) not longer recommended by International Guidelines. Since current guidelines recommend new "lipid -friendly" PI, future studies should compare regimens containing these news PIs to triple NRTI regimens. More realistically, however, there are opportunities to examine these issues in existing cohorts.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lipids; Maintenance Chemotherapy; Middle Aged; Nevirapine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Failure; Viral Load; Young Adult; Zidovudine

A growing number of associations between adverse drug reactions and alleles of the human leukocyte antigen (HLA) genes are now known. Although several models have been proposed to explain these associations, an underlying molecular basis has only recently been described. The associations between HLA-B*57:01 and abacavir hypersensitivity syndrome, and HLA-B*15:02 and carbamazepine-induced bullous skin disease have provided new insights into the mechanism associated with hypersensitivity reactions to these drugs. Here we discuss recent evidence that small molecules can interact with specific HLA to distort self-peptide presentation leading to autoimmune-like drug hypersensitivities that potentially provide clues to the mechanisms underlying other immunopathologies.

Topics: Animals; Anti-HIV Agents; Anticonvulsants; Antigen Presentation; Autoantigens; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA Antigens; Humans; Peptide Fragments; Protein Binding; Seizures; Skin

Abacavir is an effective nucleoside analog reverse transcriptase inhibitor used to treat human immunodeficiency virus (HIV) infected patients. Its main side effect is hypersensitivity reaction (HSR). The incidence of the HSR is associated with ethnicity among patients exposed to abacavir, and retrospective and prospective studies show a significantly increased risk of abacavir-induced HSR in human leukocyte antigen (HLA)-B*57:01-carrying patients. Immunological studies indicated that abacavir interacts specifically with HLA-B*57:01 and changed the binding specificity between the HLA molecule and the HLA-presented endogenous peptide repertoire, leading to a systemic autoimmune reaction. HLA-B*57:01 screening, combined with patch testing, had clinically predictive value and cost-effective impact in reducing the incidence of abacavir-induced HSR regardless of the HLA-B*57:01 prevalence in the population. Therefore, the US Food and Drug Administration (FDA) and international HIV treatment guidelines recommend a routine HLA-B*57:01 screening prior to abacavir treatment to decrease false positive diagnosis and prevent abacavir-induced HSR. The studies of abacavir-induced HSR and the implementation of the HLA-B*57:01 screening in the clinic represent a successful example of the use of pharmacogenetics for personalized diagnosis and therapy.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Testing; Histocompatibility Testing; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Precision Medicine; Translational Research, Biomedical

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Coinfection; Deoxycytidine; Dideoxynucleosides; Disease Progression; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Emtricitabine; Hepatitis C, Chronic; HIV Infections; Homosexuality, Male; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Diseases; Male; Oligopeptides; Organophosphonates; Polyethylene Glycols; Proline; Pyrrolidinones; Raltegravir Potassium; Recombinant Proteins; Ribavirin; Serine Proteinase Inhibitors; Substance Abuse, Intravenous; Tenofovir; Treatment Outcome

Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen.. From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel-Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA-requested adverse event reports of MI provided by each investigator.. The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%).. To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

Infection with Human Immunodeficiency Virus (HIV) remains a global public health problem. Although the epidemic has not been completely controlled, there was considerable progress in HIV prevention and treatment during the last 30 years. The modern prevention approaches are multi-component including also the administration of combinations of potent antiretroviral agents as a prophylaxis after occupational or non-occupational exposures to HIV. The aim of the current review is to present the chemical and pharmacological characteristics of antiretroviral drugs used in HIV prophylaxis and to describe briefly the medical management of exposures to potentially infectious body fluids.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Emtricitabine; HIV; HIV Infections; Humans; Lamivudine; Occupational Exposure; Organophosphonates; Stavudine; Tenofovir; Zidovudine

The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC.. To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs).. Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel-Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model.. Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39-1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62-1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63-2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67-1.00; P = 0.05).. This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Myocardial Infarction; Odds Ratio; Randomized Controlled Trials as Topic; Risk Factors

The introduction of combination antiretroviral therapy (cART) in 1996 dramatically changed the survival and the quality of life of people living with human immunodeficiency virus (HIV). Viral replication can be controlled by using a combination of more than 30 licensed drugs. Despite the fact that many advances have been made in the last 20 years of experience with antiretrovirals, certain needs remain to be addressed, such as the presence of chronic inflammation, the long-term side effects of newly introduced drugs and eradication. Abacavir (ABC) and lamivudine (3TC) are licensed in a fixed-dose combination to be administered once daily with other antiretroviral agents for the treatment of HIV.. This article provides an extensive review of the evidence on the combination of ABC 600 mg and 3TC 300 mg. Specifically, it discusses the chemistry-- including the phrarmacodynamics, resistance to treatment, pharmacokinetics and metabolism--and formulations available. It also looks at clinical efficacy, including safety and tolerability.. In the last few years, new data regarding human leukocyte antigen (HLA) B*5701 testing to prevent the hypersensitivity reaction due to ABC have been presented, providing a landmark in the management of adverse events in HIV, and later a previously unexpected correlation of the recent exposure to ABC with an increased risk of cardiovascular disease. This review presents the current situation with regard to the long-term efficacy and safety data on the ABC/3TC combination.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Dideoxynucleosides; HIV; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

The introduction of highly active antiretroviral therapy (HAART) as standard of care has changed the natural history of HIV infection into a manageable chronic disease requiring long-term antiretroviral (ARV) treatment. However, response to HAART is often limited by the occurrence of toxicity or by the emergence of drug resistance. Antiretroviral treatment is characterized by differing rates of adverse events and responses. Genetic variations between human beings account for a relevant proportion of this variability. A relevant number of associations between human genetic variants and predisposition to adverse events have been described and for some antiretroviral drugs a clear and casual genotype-phenotype correlation has already been established. The strong association between abacavir hypersensitivity reaction and HLA-B*5701 has been demonstrated in both observational and blinded randomized clinical trials in racially diverse populations and represents the best example of the clinical utility of pharmacogenetic screening in HIV medicine. Genotyping for HLA-B*5701 before prescribing an abacavir containing regimen has been introduced into routine clinical practice as the standard of care for all patients. Other well-established associations include CYP2B6 alleles and efavirenz central nervous system side effects, UGT1A1 alleles and atazanavir-associated hyperbilirubinemia and HLA class II allele HLA-DRB*0101 and nevirapine-associated hypersensitivity. Despite genetic associations having been described for peripheral neuropathy, lipodystrophy, hyperlipidaemia, pancreatitis and renal proximal tubulopathy, numerous barriers exist to the successful introduction of widespread genetic testing to the clinic. Future prospects point in the direction of individualization of antiretroviral therapy through insights from host genetics. The present paper is aimed to provide a comprehensive review of the published literature and to summarize the state of research in this area. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Topics: Alkynes; Anti-HIV Agents; Aryl Hydrocarbon Hydroxylases; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Dideoxynucleosides; Glucuronosyltransferase; HIV Infections; HLA-A Antigens; HLA-B Antigens; HLA-DRB1 Chains; Humans; Nevirapine; Oligopeptides; Oxidoreductases, N-Demethylating; Pharmacogenetics; Pyridines

This review focuses on current studies addressing the association of abacavir (ABC) therapy and myocardial risk in HIV-infected patients, discusses potential pathogenetic mechanisms, and suggests a preliminary algorithm for decision making regarding ABC therapy in daily clinical practise.. The D:A:D study was the first to reveal an increased rate of myocardial infarction in patients recently treated with ABC. Subsequent analyses of both cohort studies as well as prospective randomized clinical trials largely confirmed this association. Although these studies varied considerably by design and their ability to control for confounders, they provide early support that ABC therapy can increase the risk for cardiovascular disease. The pathogenesis of this association remains elusive. Preliminary cross-sectional studies suggest the involvement of inflammation associated with ABC.. Prospective studies are required to provide additional evidence for the association of ABC therapy and cardiovascular events. In individual patients with underlying high cardiovascular risk, replacement of ABC may be considered, if it can be substituted by alternative equally effective treatment.

Topics: Algorithms; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Prospective Studies; Risk Factors

Topics: Antiretroviral Therapy, Highly Active; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors

Since the presentation of the D:A:D study results at the Conference on Retroviruses and Opportunistic Infections in February 2008, 10 studies have explored the association between exposure to abacavir and the risk of myocardial infarction. Among the five larger studies, three conclude that there is an association and two that the association is not robust. Based on these studies, it is impossible to refute or confirm a causal relationship, as it is not possible to exclude remaining confounding (smoking in two of the studies, kidney function in two of the studies, cocaine and/or intravenous drug use) and selection bias in studies that report a robust association. In addition, no convincing mechanism has been described.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Cohort Studies; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Risk Assessment

Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug. Early studies identified a strong association between the MHC class I allele HLA-B*5701 and AHS. These studies suggested that HLA-B*5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B*5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B*5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B*5701 screening can largely eliminate AHS. Furthermore, skin-patch testing was used in later-generation studies to separate those patients with true immunologically mediated AHS from those with false-positive clinical diagnoses. Currently, high-level evidence suggests that HLA-B*5701 has a negative predictive value of 100% for patch-test-confirmed AHS, which is generalizable across White and Black populations. Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B*5701 screening be incorporated into routine care for patients who may require abacavir. New laboratory techniques such as PCR and flow cytometric methods, as well as an international quality assurance program, have evolved to ensure the availability of cost-effective screening methods whose consistency and standard can be maintained over time. An elegant body of basic science has evolved, which supports and complements the clinical research in suggesting that AHS is specifically and exquisitely restricted by HLA-B*5701 and mediated by CD8+ lymphocytes. Abrogating factors explaining why 45% of those carrying HLA-B*5701 can tolerate abacavir remain to be defined. The research approach applied to AHS has led to a genetic screening test being successfully implemented globally in primary HIV clinical practice. The abacavir 'example' can be applied to other drugs to facilitate the development and operationalization of genetic tests that may be useful to predict and prevent otherwise unpredictable drug reactions.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Pharmacogenetics; Syndrome

Fixed dose antiretroviral combinations (FDC) may improve therapy adherence with reduced pill burden. Abacavir and lamivudine are well-established nucleoside reverse-transcriptase inhibitors available as a once-daily FDC. Abacavir is currently considered an alternative treatment option in most established treatment guidelines based on associations with cardiovascular events and lesser efficacy in patients with higher baseline viremia.. To summarize rigorous clinical trial data and cohort studies that examine efficacy, safety and tolerability of the individual components and the FDC of abacavir-lamivudine.. Clinical trial data, post-marketing research findings and clinical cohort data were reviewed to assess the efficacy, safety and tolerability of the individual components and the FDC of abacavir-lamivudine along with recommendations from published clinical treatment guidelines.. The efficacy of abacavir-lamivudine is well documented in numerous clinical studies and treatment guidelines. The introduction of laboratory testing to identify patients at risk for hypersensitivity has decreased the incidence of these reactions. Recent findings suggest that abacavir is an alternative treatment agent with baseline HIV RNA > 100,000 copies/ml. Data related to cardiovascular events associated with abacavir are conflicting. Hepatic function should be monitored closely in HIV/HBV co-infected patients who discontinue lamivudine-containing products as severe acute exacerbations of HBV have been reported.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Combinations; Drug Monitoring; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Nevirapine; Patch Tests

A pharmacogenetic marker for abacavir hypersensitivity is rapidly being incorporated into routine medical practice following demonstration of strong clinical utility in pivotal clinical studies. As one of the few pharmacogenetic markers that have crossed from research tools to clinical adoption and utilization, the abacavir hypersensitivity pharmacogenetic marker provides a great model for demonstration of factors that are critical to successful pharmacogenetic test adoption. Several examples of novel diagnostic test implementation are reviewed with focus on factors that are critical to translation into clinical practice. Other pharmacogenetic markers that have not yet been integrated into routine clinical care are discussed and reasons for their lack of acceptance are suggested.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Models, Biological; Pharmacogenetics

To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR).. A MEDLINE (1950-October 2007) and EMBASE (1980-October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B(*)5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies.. Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review.. Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B(*)5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B(*)5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir.. Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B(*)5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans

Treatment of HIV infection has typically been carried out using two nucleoside analogs and a protease inhibitor. Such regimens can be complex and have high pill burdens. Use of alternative regimens, such as triple nucleoside-based regimens, can improve adherence and decrease toxicities associated with protease inhibitor therapy. A formulation of abacavir sulfate/lamivudine/zidovudine allows a dosing schedule of one pill twice daily. The components have performed favorably compared with protease inhibitor-based regimens, such as indinavir. Compared with efavirenz-based regimens, abacavir sulfate/lamivudine/zidovudine has not performed as well. The combination is being studied as a cornerstone for induction maintenance strategies, in which switching a patient to abacavir sulfate/lamivudine/zidovudine has been associated with similar virologic outcomes as continuing with either protease inhibitor- or efavirenz-based regimens. Administration of abacavir sulfate/lamivudine/zidovudine also avoids side effects of antiretroviral therapy, such as hyperlipidemia, but its use is associated with a hypersensitivity reaction in a small number of patients. The combination of abacavir sulfate/lamivudine/zidovudine is an important part of the HIV armamentarium. Its potency and ease of administration make it worth consideration in the treatment of HIV, either by itself or in combination with other agents.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Treatment Outcome; Zidovudine

Drug hypersensitivity has been reported to occur 100 times more commonly in those living with HIV. In the first decade of HIV treatment, this mainly involved drugs used to treat HIV-related infections but now primarily includes drugs used to treat HIV. This review focuses on the current knowledge of the epidemiology, pathophysiology and clinical features of drug hypersensitivity reactions of drugs used in the management of the HIV-infected patient.. Our understanding of the immunogenetics and host predisposition to drug hypersensitivity has been advanced considerably by the antiretroviral drugs abacavir and nevirapine. The association of abacavir hypersensitivity reaction with HLA-B*5701 has been particularly important and provides a basis for genetic screening in the clinic setting.. The increased predisposition of drug hypersensitivity disease in HIV will continue to provide a fertile ground for study of the diverse and complex processes that drive its pathophysiology. Our knowledge of drug hypersensitivity will also increase as the expanding armentarium of antiretroviral therapy is applied to more diverse populations in the developing world. The potential for widespread implementation of HLA-B*5701 screening for abacavir hypersensitivity will set an important precedent for bringing individualized medicine to the clinic and the use of genetic testing to improve drug safety.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors; Trimethoprim, Sulfamethoxazole Drug Combination

Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients. However, problems such as short-term or long-term toxicity and the development of drug resistance could necessitate a change in the therapy regimen. Whereas various HAART options with low pill burden and favourable long-term tolerability profiles are available for naive patients, treatment of experienced patients tends to be more complex and remains a challenge. Treatment with class sparing nucleoside-only regimens could be an option in this context, but the combination of zidovudine (AZT), lamivudine (3TC) and abacavir (ABC) has shown to be inferior in terms of virological efficacy compared with the standard regimen. More promising data were obtained when AZT, 3TC and ABC were intensified with tenofovir (TDF), resulting in a quadruple nucleoside therapy. This regimen has demonstrated comparable potency to a standard regimen with AZT, 3TC and efavirenz in treatmentnaive patients. Additionally, it has shown to be an efficient treatment option especially in moderately pretreated patients. This is accredited to the potency of the single components and the antagonistic selection pressure of AZT and TDF. The presence of L210W, or at least two of the mutations 41L, 67N, 70R, 215F/Y or 219Q/E, at or before baseline seems to be a predictor of non-response, whereas the presence of M184V does not impede virological response and might even be advantageous. This review summarizes current data on the combined use of AZT, 3TC, ABC and TDF in regard to virological and immunological outcome as well as genotypic predictors of response.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Organophosphonates; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure; Treatment Outcome; Viral Load; Zidovudine

Access to potent antiretroviral medications greatly reduces morbidity and mortality due to HIV/AIDS, but drug toxicity limits treatment success in many individuals. The field of pharmacogenomics strives to understand the influence of human genetic variants in response to medications. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and hsp70-hom genotypes, and among CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system symptoms. Pharmacogenomics also holds great promise to suggest novel targets for drug development. The discovery that a naturally occurring, nonfunctional variant of the HIV receptor gene CCR5 protected against HIV infection encouraged the development of CCR5 antagonists. Through continued translational and applied research, pharmacogenomics will ultimately benefit persons living with HIV worldwide by identifying new therapeutic targets and through individualized drug prescribing that is informed by human genetic testing.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Genetic Variation; HIV Infections; HIV-1; Humans; Oxazines; Pharmacogenetics; Proteins; Reverse Transcriptase Inhibitors; Treatment Outcome

Heterogeneity exists in the effectiveness and toxic effects of antiretroviral agents between individuals and populations. Although patient-related clinical variables such as age, sex and ethnic origin have been associated with drug response, inherited predispositions may have a significant effect on treatment outcome. The role of host and pathogen pharmacogenomics is gaining increasing interest in the field of both antiretrovirals in development, such as the chemokine (C-C motif) receptor 5 (CCR5) inhibitors, and in established therapies where toxicity and efficacy may be predicted. Despite numerous studies available in the literature, the interpretation of the relationship between genetic polymorphisms and clinical outcomes is often posed with many confounding variables, making clinical interpretations of these results difficult. This review summarizes the key findings in the growing knowledge between human genetics and response to antiretroviral drugs and how these findings may be effectively applied in a clinical context.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CCR5 Receptor Antagonists; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Pharmacogenetics; Reverse Transcriptase Inhibitors

The primary goal of the highly active antiretroviral treatment is to improve HIV-infected patient immune function through maintaining viral suppression. However, this treatment may lead to adverse events, some of them potentially serious. This article emphasizes on the antiretroviral therapy associated adverse events and their management recommendations, especially for serious or potentially life-threatening cases. Adverse events analyzed in this article include side effects derived from mitochondrial toxicity, abacavir hypersensitivity reaction, hepatotoxicity, skin rash and Stevens-Johnson syndrome, increased bleeding episodes in hemophilic patients and nephrotoxicity. In some cases, a high suspicion is needed because the onset symptoms may be unspecific.

Topics: Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Exanthema; Hemorrhage; HIV Infections; Humans; Liver Failure; Mitochondrial Myopathies; Stevens-Johnson Syndrome

The major trials conducted on treatment simplification included large portions of patients who had previously received monotherapy or dual therapy and were likely to have relevant mutations of resistance at baseline. These studies concluded that simplification was safe (especially when this population was excluded), with some additional risk of viral failure for subjects simplified to abacavir-based regimens. On the other hand, induction-maintenance studies and other studies which involved only patients who had started HAART as the first-line showed that simplification to abacavir was as safe as continuation of the original regimen and better accepted by the patients. The largest randomized studies of simplification that allowed extrapolation of data on the population of subjects who had never received suboptimal therapy were reviewed. Four studies failed to show significant differences in efficacy between treatment arms, while two detected significant differences in favor of the continuation arms. Simplification to abacavir led to significant decreases in cholesterol and triglyceride levels and to slight improvements in quality of life. No variations in body shape were detected, although the duration was probably insufficient and most studies did not involve adequate technology (i.e. DEXA, CT). Other, smaller studies are also presented in the review, selected for their particular design or analysis, which may contribute to a better understanding of the setting in which simplification may be a feasible option. Choosing the adequate timing and the correct patient characteristics, simplification to abacavir-based regimens is safe and prevents metabolic consequences of therapy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Drug Tolerance; HIV Infections; HIV-1; Humans; Multicenter Studies as Topic; Mutation; Randomized Controlled Trials as Topic; Safety

Consensus guidelines for the management of HIV infection recommend the use of two nucleoside analogues in combination with either a non-nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in therapy-naive patients. As adherence is crucial for treatment success, regimens with fewer pills, simpler dosing schedules and fewer adverse events have become the first choice for antiretroviral therapy. Fixed-dose combinations further improve the convenience of therapy. There are three dual-nucleoside fixed-dose combinations licensed for treating HIV-infected individuals, which include a combination of abacavir and lamivudine. This article reviews the pharmacology, efficacy, resistance profiles, safety and tolerability of abacavir focussing on its use in combination with lamivudine and discusses the role of this nucleoside backbone in antiretroviral therapy.

Topics: Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine

Abacavir and lamivudine (two nucleoside analogue reverse transcriptase inhibitors [NRTIs]), as separate formulations in combination with other antiretroviral agents, are effective in the reduction of HIV RNA levels in antiretroviral-naive patients with HIV infection, and are generally well tolerated. A fixed-dose combination tablet of abacavir/lamivudine (Epzicomtrade mark, Kivexatrade mark) has been developed for once-daily use and preliminary efficacy data are promising. Although further experience with this formulation is needed to fully determine its position in the management of HIV infection, a single, once-daily tablet that may be taken irrespective of food intake should aid adherence to treatment, a key factor in determining the success of an antiretroviral regimen. Thus, abacavir and lamivudine are two established components of first-line antiretroviral regimens for the management of HIV infection and the fixed-dose abacavir/lamivudine tablet has the potential to be an effective, easily adhered to and generally well tolerated component of first-line therapy.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine

Topics: Acquired Immunodeficiency Syndrome; Cross-Sectional Studies; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Female; HIV Infections; Humans; Hyperlipidemias; Incidence; Lamivudine; Lipodystrophy; Male; Randomized Controlled Trials as Topic; Risk Assessment

The fixed dose combination of abacavir with lamivudine represents a new treatment option for patients infected with HIV. Fixed dose combination abacavir/lamivudine has the convenience of one pill and once-daily dosing. It achieves comparable suppression of plasma HIV RNA with the pill's individual components dosed twice daily and with thymidine analogs combined with lamivudine. The combination is well tolerated, with the potential advantages of less lipoatrophy and fewer metabolic perturbations. However, the abacavir component may cause hypersensitivity reactions, which are reported in up to 8% of patients, and are potentially life threatening. Fixed dose combination abacavir/lamivudine should be considered as a viable treatment option for HIV-infected patients, particularly for those who have otherwise limited nucleoside reverse transcriptase inhibitor choices.

Topics: Animals; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; HIV-1; Humans; Lamivudine

This article provides a general introduction into the field of pharmacogenetics and discusses its opportunities and limits. Pharmacogenetic research explores genetic variability between patients to explain observed differences in effectiveness of a drug therapy or adverse event profiles. Sometimes drug therapy is unfavourable: Patients may respond only partially to a drug therapy, do not respond at all, or suffer from serious adverse events. The reasons for the varying effectiveness of a drug therapy are due to factors like absorption; metabolism, elimination and target interaction. Recent research has led to a better understanding of the molecular genetic mechanisms behind those factors. Numerous new polymorphisms have been described, for example for the beta 2-adrenergic receptor or the cytochrome which can either improve or reduce the response to drug therapy. Two polymorphisms for the tumour necrosis factor alpha have shown to be associated with an increased risk of serious adverse events (hypersensibility: fever, rash, gastrointestinal symptoms) if treated with abacavir (HIV-treatment). Pharmacogenetic tests provide information about certain polymorphisms and raise the hope for an individualized pharmacotherapy. Yet, not only genetic but also environmental factors influence the effectiveness of a therapy. Even though results from research implies that pharmacogenetics has a great potential to maximize the effectiveness of pharmacotherapy and to reduce the incidence of drug-related adverse events, extensive clinical research both on effectiveness and costs is required to assess the true benefits of these exciting new technologies.

Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cohort Studies; Dideoxynucleosides; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Male; Mutation; Pharmacogenetics; Polymorphism, Genetic; Prognosis; Research; Reverse Transcriptase Inhibitors; Trastuzumab

High rates of early virologic failure associated with the emergence of the K65R mutation in HIV-1 reverse transcriptase (RT) have been reported among HIV-infected patients who received novel, tenofovir-containing, triple-nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) regimens as their initial therapy. This review surveys the findings of prospective and retrospective studies in this regard, examines the significance of the K65R mutation and other factors associated with reports of early virologic failure among patients receiving tenofovir-containing NRTI/NtRTI regimens, and discusses clinical approaches to preventing and managing HIV drug resistance and treatment failure associated with the K65R mutation.

Topics: Adenine; Clinical Trials as Topic; Dideoxynucleosides; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; Humans; Mutation; Organophosphonates; Prospective Studies; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure

The triple combination tablet containing lamivudine (150 mg), zidovudine (300 mg) and abacavir (300 mg, as abacavir sulfate) is a new formulation of three nucleoside analogue reverse transcriptase inhibitors. Two studies in treatment-naive patients (one double-blind, one nonblind) have reported that lamivudine/zidovudine (dual combination tablet) plus abacavir showed efficacy similar to that of lamivudine/zidovudine plus indinavir. In both studies, similar numbers of patients in each treatment group had plasma HIV RNA levels 400 copies/mL, was reported in 22% of patients in both treatment groups at week 48. Treatment-naive patients receiving lamivudine/zidovudine/abacavir combination therapy experienced several adverse events, including nausea, malaise/fatigue and vomiting.

Topics: Administration, Oral; Anti-HIV Agents; Biological Availability; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Treatment Outcome; Zidovudine

Research into the toxic effects of antiretroviral therapy has made tremendous progress, particularly over the 5 years since the earliest descriptions of the lipodystrophy syndrome. In particular, the contribution of specific antiretroviral drugs to these toxicity syndromes is becoming clearer, along with their pathophysiological mechanisms. This knowledge can now direct research on host genetic factors that may significantly influence the risk of both short-term and long-term toxicities. At present, the genetic association with abacavir hypersensitivity appears sufficiently strong to consider pharmacogenetic testing in clinical practice, although further corroborative research is still needed. The future will see increasing use of both pharmacogenetics (the genetic basis for variation in the response to specific medications) and immunogenetics (the genetic basis for variation in the response to specific antigens). The identification of an increasing number of genetic associations with drug efficacy/toxicity may, or may not, result in widespread genetic testing, but it will certainly increase our understanding of the mechanisms of both desirable and adverse drug effects and inform drug development.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Dideoxynucleosides; HIV Infections; HIV Protease Inhibitors; HLA-B Antigens; Humans; Pharmacogenetics; Predictive Value of Tests; Reverse Transcriptase Inhibitors

Drug hypersensitivity is a major problem in HIV medicine. These reactions limit the choice of antiretrovirals that can be used in a patient and, at times, can lead to failure to administer an adequate regimen. Hypersensitivity reactions occur in a minority of patients, but represent a high cost both to the patient and to health services. Our current understanding of these reactions is based on the hapten and the danger hypotheses, which state that a drug signal by itself is insufficient to induce an immune response but must be accompanied by co-stimulatory or danger signals. Furthermore, individual susceptibility to a hypersensitivity reaction may be determined by genetic factors. In this review, we explore our understanding of the immunological mechanisms of hypersensitivity to drugs used in HIV-positive patients, by using sulphamethoxazole and abacavir as paradigms. A deeper understanding of the mechanism(s) of these reactions will help us in their prevention, diagnosis and treatment.

Topics: Anti-Bacterial Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; Trimethoprim, Sulfamethoxazole Drug Combination

The use of alternative nucleoside reverse transcriptase inhibitors (NRTIs) to the thymidine analogues stavudine (d4T) and zidovudine(ZDV) has been advocated as a means of limiting long-term NRTI-associated toxicity, particularly the development of lipoatrophy or fat wasting. This approach reflects an increasing knowledge of the distinct toxicity profiles of NRTI drugs. However, recent clinical trials have demonstrated that the use of thymidine analogue NRTIs and newer alternative backbone NRTIs, such as tenofovir (TNF) and abacavir (ABC), is associated with comparable short-term efficacy and tolerability. Given the importance of toxicity profile differences in determining clinical management, it is important to recognise that d4T and ZDV cary significantly different risks for long-term NRTI toxicity. Recognising that all NRTIs, including thymidine analogues, have individual toxicity profiles provides a more appropriate basis for selecting optimal antiretroviral therapy. The safety and efficacy of TNF and ABC are also reviewed here, although the available data provide only limited knowledge of the long-term effects of these drugs in terms of toxicity and antiviral durability.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-Associated Lipodystrophy Syndrome; Humans; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Time Factors

CIRCUMSTANCES AND CHARACTERISTICS: The risk of toxiderma is greater in patients infected by the human immunodeficiency virus (HIV). The most common toxidermas are maculopapular exanthema and drug hypersensitivity reactions. These toxidermas are predominantly observed with non-nucleoside reverse transcriptase analogs (nevirapine, efavirenz) and abacavir. Toxiderma has also been observed with other nucleoside reverse transcriptase analogs (zalcitabine) and protease inhibitors. REGARDING SEVERITY: The toxidermas observed are usually benign (maculopapular exanthema) and do not always require suspension of the treatment. However, certain toxidermas (Stevens-Johnson syndrome, Lyell syndrome and drug hypersensitivity syndrome) may be life-threatening and therefore contraindicate the continuation of treatment and also its sudden reintroduction. PREVENTION AND PRACTICAL APPROACH: Several studies have assessed the risk factors for toxiderma induced by nevirapine and hypersensitivity reactions to abacavir. The practical approach varies depending on the drug responsible, the clinical form of the toxiderma and the possible alternatives.

Topics: Alkynes; Anti-HIV Agents; Anti-Inflammatory Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Exanthema; Histamine H1 Antagonists; HIV Infections; HIV Protease Inhibitors; Humans; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Risk Factors; Steroids; Stevens-Johnson Syndrome

Switch studies have been carried out to explore changes in side effects in adherence. Discontinuing the protease inhibitor (PI) component of highly active antiretroviral therapy (HAART) regimen is often associated with improved adherence and improved quality of life. Following switching from a PI to a non-nucleoside reverse transcriptase inhibitor or abacavir, there is however a clear trend toward an improved metabolic profile particularly in insulin resistance and triglyceride levels when patients discontinue their PI. Peripheral wasting is likely to be associated with nucleoside analogues and for individuals with isolated fat accumulation, modification of HAART is not recommended. Virological suppression can be maintained following switch if adequate suppression of the virus has been achieved for at least six months prior to switch and the patient has not been previously exposed to suboptimal HAART. Discontinuing the PI preserves this class of agents for future use. Switching however may be associated with other side effects; hypersensitivity, skin rashes, hepatic or neuropsychiatric events.

Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV Protease Inhibitors; Humans; Lipodystrophy; Metabolic Diseases; Nevirapine; Oxazines; Patient Compliance; Reverse Transcriptase Inhibitors

To evaluate the efficacy and safety of simplified maintenance therapy (SMT) compared with continued protease inhibitor (PI) therapy.. Meta-analysis of nine randomized controlled trials in which 833 patients were switched to SMT (abacavir, efavirenz or nevirapine) and 616 continued PI, assessing virologic failure (primary outcome), discontinuation of therapy for reasons other than virologic failure, CD4 cell count, total plasma cholesterol and triglycerides.. The risk ratio for virologic failure for SMT compared to continued PI was 1.06 [95% confidence interval (CI) 0.58-1.92; test for homogeneity P = 0.01] for SMT, 2.56, (95% CI, 1.17-5.64) for abacavir, 0.83 (95% CI, 0.36-1.91) for efavirenz and 0.54 (95% CI, 0.29-1.02) for nevirapine. The risk ratio for premature discontinuation of therapy with SMT was 0.61 (95% CI, 0.48-0.77; test for homogeneity P < 0.10). The difference in absolute mean cholesterol for SMT compared to continued PI was -0.15 mmol/l, (95% CI, -0.40 to 0.09; test for homogeneity P < 0.01) for SMT, -0.51 mmol/l (95% CI, -0.70 to -0.33) for abacavir, 0.22 mmol/l (95% CI, 0 to 0.43) for efavirenz and -0.19 mmol/l (95% CI, -0.48 to 0.09) for nevirapine.. Current evidence suggests that SMT with abacavir rather than continued PI increases the risk of virologic failure, this increased risk may be confined to patients with prior mono or dual therapy with reverse transcriptase inhibitors. There is not enough evidence on whether SMT with efavirenz and nevirapine influences the risk of virologic failure. SMT with any of the three drugs reduces the risk of discontinuation of therapy, and SMT with abacavir reduces plasma cholesterol.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cholesterol; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Odds Ratio; Protease Inhibitors; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Triglycerides

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Delayed-Action Preparations; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Monitoring; Emtricitabine; Furans; HIV Infections; Humans; Lamivudine; Nevirapine; Oligopeptides; Organophosphates; Organophosphonates; Organophosphorus Compounds; Oxazines; Pyridines; Randomized Controlled Trials as Topic; Stavudine; Sulfonamides; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

Although the reduction in HIV-1-related deaths with highly active antiretroviral therapy (HAART) is similar in adults and children, the extent of the changes in two important surrogate markers HIV-1 RNA levels and CD4+ T cell counts, differs widely. In most paediatric studies virological response rates to HAART are inferior to those in adults. This review provides an overview of the paediatric clinical studies using HAART and seeks to improve the understanding of factors that may contribute to success or failure of HAART in children. An overview of all current articles on paediatric clinical trials using HAART is provided. 23 papers were available. HIV-1 RNA loads and CD4+ T cell counts were used as primary outcome measures. Virological response rates were highly variable, both among the different antiretroviral drugs but also among different studies using the same medication. Four studies in which dosages of the administrated protease inhibitor (PI) were adjusted after pharmacokinetic evaluation had superior virological response rates compared with those in which fixed dosages were used. Immunological response rates were more uniform than virological responses. In almost all studies increases of CD4+ T cell counts are reported independent of the extent of the virological response. Side-effects of HAART were generally mild, transient, and of gastrointestinal origin. Significant percentages of patients with serum lipid abnormalities were reported in three paediatric studies. However, signs of clinical lipodystrophy were not observed. The inferior virological response rates, which have been reported in HIV-1 infected children treated with HAART form a reflection of the challenges that are encountered in the treatment of these children. Difficulties with adherence and with the pharmacokinetics of PIs in children require an intensive, child-adjusted approach. A practical approach to therapy in institutions without tertiary care facilities may be induction therapy with a lopinavir containing regimen (lacking a need for therapeutic drug monitoring), to reduce high viral load levels followed by an easily tolerated maintenance regimen, for example containing abacavir or nevirapine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir

Nucleoside reverse transcriptase inhibitors (NRTIs) comprise the first class of drug with proven antiretroviral efficacy against HIV-1, and the first in which drug resistance was reported. Ongoing research in the area of NRTI resistance and cross-resistance contributes much to what we know about the failure of antiretroviral therapy. The genetic mutation patterns responsible for resistance to the available NRTIs have been well documented. This information is being used to plan rational drug therapy. Furthermore, it serves as the standard against which to evaluate response patterns to multiple-drug regimens, ultimately enabling more accurate prediction of outcome with combination therapies. Other features of NRTI resistance, such as the theoretic reversal of zidovudine resistance associated with the M184V mutation or the powerful influence of the Q151M multiple-drug resistance mutation, have revealed the unpredictable nature of HIV resistance and how much we still need to learn. Although NRTIs are the cornerstone of antiretroviral therapy at present and are used to control disease progression for extended periods, it is clear that eventually resistance occurs with all antiretroviral regimens. Future research into NRTI-resistance mutations, mutational interactions, treatment sequencing, and viral fitness and fidelity will continue to refine our understanding of drug resistance and improve our ability to delay or eliminate resistance and advance HIV control.

Topics: Dideoxynucleosides; Disease Progression; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Reverse Transcriptase Inhibitors; Zidovudine

A near-fatal hypersensitivity reaction to abacavir developed in a 62-year-old HIV-seropositive man who had been sensitized 17 months before presentation. Six days after he was rechallenged, acute respiratory distress developed, requiring mechanical ventilation for 2 weeks. Four days after extubation, he was again rechallenged. Hours later, the patient experienced anaphylactic shock, requiring mechanical ventilation for 3 weeks, aggressive volume resuscitation, and vasopressor support. Recovery was complicated by acute tubular necrosis, digital necrosis, and a GI bleed. This report reviews the mechanisms of action, efficacy, and adverse reactions of abacavir and illustrates the danger of serially rechallenging patients with this agent.

Topics: Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

In October 2000 a meeting was convened by DuPont Pharma in Scotland to discuss the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy. The Round Table meeting focused on comparisons between efavirenz and nevirapine in clinical studies and clinical practice, and the manuscripts published in this supplement report the most salient points from the presentations and discussions.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; Humans; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors

Abacavir (ABC) is a potent nucleoside reverse transcriptase inhibitor (NRTI) used in multi-drug antiretroviral regimens and in combination with other NRTIs, protease and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) in both treatment naive and treatment experienced patients.. Resistance to ABC has been demonstrated in vitro and in vivo. Patterns of emerging mutations may vary when ABC is combined with other NRTIs relative to the mutations observed in monotherapy. Additionally, thymidine NRTIs may select for mutations that, while not selected for by ABC, may confer diminished susceptibility and diminished clinical response to ABC.. Resistance and clinical data indicate that ABC may be a suitable component of initial regimens and second or subsequent lines of therapy. It may be used as a substitution agent for persons wishing to discontinue protease inhibitor therapy who have not previously experienced viral rebound on NRTI therapy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; Humans; Mutation; Reverse Transcriptase Inhibitors; Treatment Outcome

To develop an abacavir hypersensitivity reaction management protocol for the University of Oklahoma Health Sciences Center.. Conference abstracts, published literature, and manufacturer-provided materials were reviewed to define the syndrome and manifestations and to recommend steps to take when a patient develops abacavir-related reactions.. Initial education, formalized contact and response mechanism, and intervention levels were incorporated into a protocol for clinicians.. Abacavir, a newly approved agent for the treatment of HIV, has been associated with a fatal hypersensitivity reaction. Our protocol provides a mechanism to minimize progression of abacavir hypersensitivity reaction by providing a formalized management procedure.

Topics: Anti-HIV Agents; Contraindications; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

Abacavir is a carbocyclic 2'-deoxyguanosine nucleoside analogue. It is metabolised intracellularly to a 2'-deoxyguanosine nucleoside analogue which competitively inhibits HIV reverse transcriptase and terminates proviral DNA chain extension. In double-blind trials in antiretroviral therapy-experienced or -naive patients, reductions in HIV RNA levels were greater and more prolonged in patients receiving abacavir in combination with other antiretroviral drugs than in those receiving placebo in combination with the same agents. Furthermore, abacavir in combination with lamivudine and zidovudine reduced viral load to below detectable levels in a proportion of patients, and to a similar extent to the protease inhibitor indinavir in combination with lamivudine and zidovudine. Greatest viral load reductions were seen in antiretroviral therapy-naive patients. Preliminary results suggest that the viral suppression achieved with a protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) can be maintained as effectively with abacavir in combination with 2 NRTIs as it can be by continuing the protease inhibitor-containing treatment regimen. Initial virological data from studies of combination regimens including abacavir and protease inhibitors appear promising but larger controlled trials are required to confirm these observations. Nausea is the most frequently reported adverse event in patients receiving abacavir-containing combination therapy. Adverse events tend to be reported most frequently soon after starting treatment; the majority of events are mild or moderate in intensity and transient. Other adverse events reported in >5% of patients include vomiting, malaise and fatigue, headache, diarrhoea, sleep disorders, cough, anorexia and rash. A major cause of abacavir treatment discontinuation is the development of a hypersensitivity reaction which has been reported in 3 to 5% of patients. The reaction usually occurs within 6 weeks of commencing treatment, shows evidence of multiorgan system involvement and typically includes fever and/or rash. Symptoms resolve rapidly after discontinuation of treatment. Continuing treatment or rechallenge can result in more severe symptoms, life-threatening hypotension and even death.. Abacavir used in combination with other antiretroviral drugs effectively reduces viral load in both adults and children with HIV infection. Although these responses are greatest in individuals with little or no previous antiretroviral treatment, useful responses are still sometimes achieved in heavily pretreated individuals. Abacavir in combination with lamivudine and zidovudine provides a simple and convenient dosage regimen which is generally well tolerated, able to produce sustained suppression of viral replication and has the advantage of sparing other classes of antiretroviral drugs for subsequent use. This triple combination represents an alternative antiretroviral regimen for patients intolerant to protease inhibitors or those wishing to retain the option of protease inhibitors for later use. Further clinical studies are needed to define the activity of abacavir in combination with protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

Topics: Animals; Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance; Drug Therapy, Combination; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Interactions; HIV Infections; HIV-1; Humans; Oxazines; Reverse Transcriptase Inhibitors

Topics: Adenine; Alkynes; Benzoxazines; Cyclopropanes; Delavirdine; Dideoxynucleosides; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Nevirapine; Organophosphonates; Oxazines; Prodrugs; Reverse Transcriptase Inhibitors; Soman; Uracil

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; HIV; HIV Infections; Humans; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; Virus Latency; Virus Replication

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

Abacavir is a nucleoside analogue reverse transcriptase inhibitor (NRTI). It has a good oral availability and penetrates the CNS. The metabolism of abacavir is not dependent on cytochrome P450 thus avoiding significant drug-drug interactions. It has an antiviral potency comparable to that of protease inhibitors (PIs) or to dual nucleoside combinations. In addition, evidence has shown that it is effective in decreasing viral load and increasing CD4 count in HIV-infected patients, especially NRTI-naïve patients. Abacavir has an acceptable tolerability profile, although hypersensitivity reactions lead to discontinuation of therapy in approximately 3% of patients. Abacavir has a potential role in first- and second-line combination regimens and as part of a PI-sparing regimen.

Topics: Anti-HIV Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine

With longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with an increased risk of myocardial infarction, but the mechanism is unknown. Additionally, abacavir may be obesogenic which could mediate an additional risk factor of CVD. We aim to investigate if discontinuation of abacavir will have a favourable impact on body weight and cardiac parameters in PLWH.. Randomised, controlled, superiority trial of virologically suppressed PLWH on dolutegravir, abacavir and lamivudine (DTG/ABC/3TC) for ≥6 months. In total, 70 PLWH will be randomised 1:2 to either continue DTG/ABC/3TC or to switch to dolutegravir and lamivudine (DTG/3TC) providing the power of 80% at alpha 5% to detect a mean difference in weight change of 2 kg (Δ) given an SD of 2.7 kg. Follow-up will be 48 weeks. Data will be collected at baseline and week 48. Primary outcome will be change in mean body weight from baseline to week 24 and 48 evaluated in a linear mixed model. Secondary outcomes will be changes in cardiac, inflammatory and metabolic parameters, fat distribution, coagulation, endothelial, platelet function, quality of life and virological control from baseline to week 48. Measurements include CT of thorax and abdomen, external carotid artery ultrasound, liver elastography and dual energy X-ray absorptiometry and blood analysis. Plasma HIV RNA will be measured at baseline, week 4, 24 and 48. Forty participants (20 from each arm) will be included in a substudy involving cardiac MRI at baseline and week 48. Twenty non-HIV-infected controls will be included with a single scan to compare with baseline scan data.. Result from this study will lead to a better understanding of the association between antiretroviral therapy and the impact on weight and risk of CVD. Findings will be useful for both clinicians and PLWH in the guidance of a more individualised HIV treatment. Results from the main study and the substudies will be submitted for publication in a peer-reviewed journal(s). The AVERTAS study is approved by the Ethics Committee of the Capital Region, Denmark (H-20011433), Danish Medicines Agency (EudraCT no. 2019-004999-19) and Regional Data Protection Centre (P-2020-207).. Pre-results registration at ClinicalTrials.gov Identifier: NCT04904406, registered 27 May 2021.. Protocol version 9.0, 4 April 2023, approved 10-05-2023 by Ethics Committee of the Capital Region, Denmark (H-20011433). Danish Medicines Agency (EudraCT no. 2019-004999-19). Regional Data Protection Centre (P-2020-207) ClinicalTrials.gov.

Topics: Body Composition; Body Weight; Cardiovascular Diseases; Denmark; HIV Infections; Humans; Lamivudine; Quality of Life

Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.. The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.. Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.. The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Infant, Newborn; Lamivudine; Lopinavir; Ritonavir

Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG).. We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy.. Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively].. Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Topics: Adult; Anti-HIV Agents; Bone Density; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Kidney; Lamivudine; Middle Aged; Oxazines; Patient Reported Outcome Measures; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Tenofovir

In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies.. We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956.. 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study.. These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance.. Gilead Sciences.

Topics: Adenine; Adult; Aged; Alanine; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Tenofovir; Treatment Outcome; Young Adult

Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.. Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.. In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.. Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.. EUDRACT number: 2011-005973-21.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Delayed Diagnosis; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Raltegravir Potassium; Ritonavir

The WHO recently recommended the use of a new first-line ART containing dolutegravir. We investigated the efficacy of NRTI backbones (tenofovir or abacavir with a cytosine analogue) in low- and middle-income countries where there is significant prior exposure to antiretrovirals and drug resistance to NRTIs.. Within the treatment-as-prevention study in South Africa, we selected participants with available next-generation sequencing (NGS) data for the HIV-1 pol gene at trial entry; they were either ART initiators (n = 1193) or already established on ART (n = 94). NGS of the HIV-1 pol gene was carried out using MiSeq technology; reverse transcriptase drug resistance mutations (DRMs) were detected at 5% (DRM5%) and 20% (DRM20%) for all 1287 participants. Genotypic susceptibility was assessed using the Stanford HIVDB resistance interpretation algorithm.. NRTI DRM20% and DRM5% were detected among 5/1193 (0.4%) and 9/1193 (0.8%) of ART initiators, respectively. There was tenofovir exposure in 73/94 (77.7%) of those established on ART, with full susceptibility to abacavir in 57/94 (60.6%) and 56/94 (59.6%) for DRM20% and DRM5%, respectively, while 67/94 (71.3%) and 64/94 (68.1%) were fully susceptible to tenofovir, respectively. The differences between tenofovir and abacavir were not statistically significant at the 20% or 5% variant level (P = 0.16 and 0.29, respectively). NGS detection of variants at the 5% level increased detection of K65R in both naive and treated groups. One of 607 integrase sequences carried a DRM20% (Q148R).. Dolutegravir with a cytosine analogue plus tenofovir or abacavir appears to have similar efficacy in South Africans naive to ART. NGS should be considered in HIV drug resistance surveillance.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cytosine; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones; South Africa; Tenofovir; Viral Load; Young Adult

We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy.. MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/μL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart.. Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], -5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy.. Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection.. NCT02596334 and EudraCT 2015-002853-36.

Topics: Adult; Anti-HIV Agents; Confidence Intervals; Dideoxynucleosides; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones

Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96.. This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930.. Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group.. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance.. Gilead Sciences, Inc.

Topics: Adenine; Alanine; Amides; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Male; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load

Describe the pharmacokinetics (PK) of the antiretroviral drugs abacavir and lamivudine in malnourished paediatric patients and relate to viral load outcomes after 12 and 48 weeks of treatment.. Severely malnourished human immunodeficiency virus-infected children were randomized to early (within 14 days) or delayed (after nutritional recovery) initiation of antiretroviral treatment (ART) using World Health Organization weight-band dosages. Abacavir and lamivudine concentrations were measured as a secondary objective on day 1 and day 14 and patients were followed-up to week 48. Population PK of abacavir and lamivudine were described using NONMEM.. In total, 623 abacavir and 627 lamivudine concentrations were collected from 75 paediatric patients aged 0.1-10.8 (median 1.4) years. Abacavir PK was described by a 2-compartment model, patients randomized to early ART showed increased bioavailability of 31%. Apparent clearance (CL/F, L/h/7 kg) of abacavir increased from day 1 to day 14 from 3.33 (95% confidence interval 2.71-4.12) to 5.86 (95% confidence interval 4.78-7.3). A 1-compartment model described lamivudine PK, variability on CL/F was explained by maturation with age, with age at half-matured CL/F being 4 months. For both drugs allometrically scaled total body weight was related to CL/F and apparent volume of distribution. PK exposure did not correlate with virological outcomes or death at 12 or 48 weeks.. Increases in Abacavir's CL/F between day 1 to day 14, bioavailability and PK variability with early start of ART was found in this cohort of severely malnourished children; however, these changes did not influence virological outcomes. The study supports the use of weight-band dosage tables.

Topics: Anti-HIV Agents; Biological Availability; Body Weight; Child; Child Nutrition Disorders; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Follow-Up Studies; HIV; HIV Infections; Humans; Infant; Lamivudine; Male; Models, Biological; Nutritional Support; Severity of Illness Index; South Africa; Time Factors; Time-to-Treatment; Treatment Outcome; Viral Load

Abacavir has replaced stavudine in antiretroviral therapy (ART) regimens because it has largely been phased out as a result of toxicity concerns; this loss has reduced further the already-limited drug options for children. Few data regarding virologic and metabolic outcomes among children who undergo substitution of stavudine exist. We evaluated the effects of preemptive substitution of abacavir for stavudine in children initially without lipodystrophy and virally suppressed on a stavudine-containing regimen.. At Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa, virally suppressed human immunodeficiency virus (HIV)-infected children ≥36 months of age without lipodystrophy were randomly assigned to continue taking stavudine as part of their ART regimen (n = 106) or to have abacavir substituted for stavudine (n = 107). The children were followed for 56 weeks after randomization in the context of a larger trial of treatment options for ART-experienced children.. The mean age of the children was 4.3 years, and the mean duration of ART before random assignment was 3.5 years. No differences in virological outcomes, CD4 response, growth, or dyslipidemia were noted between the stavudine and abacavir groups. By 56 weeks, children in the abacavir group had less clinically detected lipodystrophy (4.7% vs 16%, respectively), a higher proportion of leg fat relative to total fat (0.243 vs 0.230, respectively; P = .006), and a lower trunk/leg-skinfold ratio (0.547 vs 0.569, respectively; P = .003) than the children in the stavudine group.. Substituting abacavir for stavudine did not compromise virological response to treatment and was associated with significantly less lipodystrophy. These results support recommendations that favor abacavir in this population.

Topics: Anthropometry; Anti-HIV Agents; Body Composition; CD4 Lymphocyte Count; Child, Preschool; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Infant; Lipodystrophy; Male; South Africa; Stavudine; Viral Load

Altered platelet function has been proposed as an underlying mechanism to explain increased risk of myocardial infarction in people living with HIV associated with use of the nucleoside reverse transcriptase inhibitor abacavir (ABC). We aimed to examine changes in platelet biomarkers in people living with HIV switching from ABC.. In a prospective, 48-week substudy of virally suppressed HIV-1-positive subjects randomized to remain on ABC/lamivudine (ABC/3TC) or switch to tenofovir disoproxil fumarate/emtricitabine, we measured soluble glycoprotein VI (sGPVI), soluble P-selectin, soluble CD40 ligand and von Willebrand factor in plasma collected over time and assessed differences using mixed effect models.. Of 312 randomized participants, 310 were included in the analysis. Mean (SD) age 46.4 (9.3) years, 262 (85%) men and 201 (65%) white. At baseline, there was no significant between-group difference in sGPVI [tenofovir disoproxil fumarate/emtricitabine 3.75 (0.25) versus ABC/3TC 3.61 (0.22) ng/ml, P = 0.69]. Greater increases in sGPVI from baseline to week 48 occurred in those switched from ABC/3TC (effect size +0.57 ng/ml; 95% confidence interval, 0.2-0.94; P = 0.003). There was no significant baseline difference or change overtime in soluble P-selectin, soluble CD40 ligand or von Willebrand factor between groups.. The significant increases in sGPVI that occur with a switch from ABC/3TC are suggestive of changes in platelet function centred on platelet/collagen interactions and potentially represent an underlying mechanism to explain increased risk of myocardial infarction with ABC.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Blood Platelets; CD40 Antigens; Collagen; Dideoxynucleosides; Drug Substitution; Female; HIV Infections; Humans; Male; Middle Aged; P-Selectin; Platelet Membrane Glycoproteins; Prospective Studies; Tenofovir; Treatment Outcome; von Willebrand Factor; Young Adult

Ischemic cardiovascular events are a relevant cause of morbidity and mortality in HIV-infected patients. Use of abacavir (ABC), a nucleoside analog reverse transcriptase inhibitor, has been associated with increased risk of myocardial infarction (MI) and with platelet hyperreactivity. We explored whether low-dose aspirin reduces in vivo platelet activation and platelet hyperreactivity induced by ABC in HIV-infected subjects.. In a randomized, placebo-controlled, cross-over study forty HIV-infected patients with ABC-associated platelet hyperreactivity, defined by a score based on laboratory variables reflecting in vivo platelet activation and ex vivo platelet hyperresponsiveness, were randomized to aspirin 100 mg daily for 15 days with subsequent cross-over to placebo for additional 15 days or placebo for 15 days with subsequent cross-over to aspirin for further 15 days. In vivo and ex vivo platelet activation markers were measured at day 15 and 30. One group of healthy subjects, one of untreated HIV infected-patients and one treated without ABC, were studied concomitantly. Serum TxB. Aspirin reduces ABC-induced in vivo platelet activation and platelet hyperreactivity in HIV-infected patients, however without normalizing them. Whether the observed reduction of platelet activation is sufficient to prevent cardiovascular events requires a prospective trial.

Topics: Anti-HIV Agents; Aspirin; Blood Platelets; Cohort Studies; Cross-Over Studies; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies

Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection.. In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120.. Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group.. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection.. Gilead Sciences.

Topics: Adult; Aged; Amides; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Substitution; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Seropositivity; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Sustained Virologic Response; Tenofovir; Viral Load; Young Adult

Combination abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) is approved as a first-line treatment for antiretroviral naïve patients. This report investigated the immunovirological outcome and total HIV-1 DNA decay in a small cohort of naïve HIV-1-positive patients treated with this regimen. In the presence of viral suppression and increased lymphocyte T CD4+ cells, the quantitative analysis of total HIV-1 DNA content revealed a significant decay after 12 months of treatment. Subsequently, we deintensificated the treatment of these patients from (ABC/3TC/DTG) to lamivudine plus dolutegravir (3TC/DTG) after 12 months of virological suppression, as a strategy of "induction-maintenance" therapy. The analysis of HIV-1 RNA viral load, total HIV-1 DNA, CD4+ T lymphocyte count and CD8+ HLA-DR+ T lymphocyte percentage after a mean 3.5 months of therapy deintensification showed no significant difference with respect to data detected after 12 months of ABC/3TC/DTG treatment in the presence of continuous viral suppression. These results indicate that the deintensification of highly active antiretroviral therapy (HAART) from ABC/ 3TC/DTG to 3TC/DTG effectively controls HIV-1 replication and in the early period does not induce any significant variations of total HIV-1 DNA. This suggests that HAART deintensification might be proposed as a therapeutic evolution in the treatment of HIV-1 infection.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; DNA, Viral; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Viral Load; Young Adult

It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia.. We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n  =   134) versus abacavir ( n  =   135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24.. Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P  ≥   0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r  =   -0.22, P  =   0.028) and week 48 ( r  =   -0.26, P  =   0.010), but not at week 96 ( r  =   -0.14, P  =   0.18).. Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.

Topics: Adult; Anti-HIV Agents; Bone Density; Dideoxynucleosides; Female; Glomerular Filtration Rate; Hip; HIV Infections; Humans; Hypophosphatemia, Familial; Male; Middle Aged; Phosphates; Spine; Tenofovir; Young Adult

Simplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).. The STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24.. Of 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART.. Data demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Canada; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Treatment Outcome; United States; Viral Load

Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.. The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.. Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.. The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.. ViiV Healthcare.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome

Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues.. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP.. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029).. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL.. NCT01900015.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Mass Index; Body Weight; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Elasticity Imaging Techniques; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Raltegravir Potassium; Tenofovir; Triglycerides; Waist-Hip Ratio

Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression.. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm.. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively.. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy.. NCT02159599.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Medication Therapy Management; Middle Aged; Ritonavir; RNA, Viral; Tenofovir; Viral Load

WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz.. In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957.. Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00).. All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines.. European Developing Countries Clinical Trials Partnership.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Nevirapine; Stavudine; Tablets; Uganda; Zambia; Zidovudine

To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum.. A nonrandomized, open-label, multicentre, phase-IV study.. HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care were included. Intensive 24-h pharmacokinetic sampling was performed during the third trimester and at least 2 weeks after delivery. Pharmacokinetic parameters were calculated by noncompartmental analysis. Paired cord blood and maternal blood samples were taken at delivery when feasible.. A total of 14 women were included in the analysis. Geometric mean ratios (90% confidence intervals) of third trimester versus postpartum were 1.05 (0.92-1.19) for AUC0-24h and 1.00 (0.83-1.21) for Cmax. The median (range) ratio of abacavir cord plasma to maternal plasma was 1.0 (0.7-1.0, n = 3). Viral load at the third trimester visit was less than 50 copies/ml in 13 participants (93%; one unknown). In total, 13 (93%; one unknown) children were tested HIV-negative.. The pharmacokinetics of abacavir 600 mg q.d. during pregnancy are equivalent to postpartum. No dose adjustments are required during pregnancy and similar antiviral activity is expected.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Infectious

Antiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes.. Children taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events.. Six hundred and sixty-nine children (median 5 years, range 1-16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference -1.6% (95% confidence interval -8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15).. Once-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical, immunological and safety outcomes. Abacavir + lamivudine provides the first once-daily nucleoside backbone across childhood that can be used to simplify ART.

Topics: Adolescent; Africa; Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Resistance, Viral; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Immune Reconstitution; Infant; Lamivudine; Male; Medication Adherence; Sustained Virologic Response; Treatment Outcome

There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination.. Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy.. Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21-59.78 years). The mean age was 59 years (95% CI: 58.21-59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6-100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events.. Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coinfection; Dideoxynucleosides; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Sofosbuvir; Treatment Outcome; Viral Load

The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI).. An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/μL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/μL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59).. For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm.. A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Topics: Adult; Aged; Anti-HIV Agents; Belgium; CD4 Lymphocyte Count; Clinical Protocols; Dideoxynucleosides; Disease Progression; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lipids; Male; Middle Aged; Netherlands; Prospective Studies; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study.. As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance.. From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3.0 (1.3-4.3) in the NtRTI group and 3.0 (1.0-4.3) in the raltegravir group. The median sGSS in the NtRTI group was 1.0 (0.5-1.8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2.18, 95%CI 1.07-4.47; p=0·03) and week 48 (2.49, 1.09-5.69; p=0.03), baseline plasma viral load greater than 100,000 copies per mL (3.43, 1.70-6.94; p=0.0006), baseline gGSS >4.25 (4.73, 1.94-11.6; p=0.0007), and being Hispanic (3.13, 1.21-8.13; p=0.02) or African (3.49, 1.68-7.28; p=0.0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2.47, 95% CI 1.02-5.99; p=0.05), baseline log10 viral load (1.83, 1.12-2.97; p=0.02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3.18, 1.12-9.02; p=0.03).. Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable.. University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Ritonavir; South Australia; Tenofovir; Treatment Outcome; Viral Load; Young Adult

The aim of the study was to investigate the effect of a simplified regimen, in terms of reducing pill burden, dietary requirements and possible adverse effects, on patients' adherence, treatment satisfaction and quality of life (QoL).. Antiretroviral-naïve patients who achieved a viral load < 50 HIV-1 RNA copies/ml after induction therapy with twice-daily (bid) lopinavir/ritonavir (LPV/r) and fixed-dose zidovudine (ZDV)/lamivudine (3TC) (CBV) were randomly assigned to continue CBV/LPV/r or switch to fixed-dose ZDV/3TC/abacavir (TZV). Patients completed standardized questionnaires on adherence, treatment satisfaction and QoL at randomization (between weeks 12 and 24) and at weeks 48, 72 and 96.. Patients on CBV/LPV/r were more likely to have skipped medicines in the last week (P = 0.035) and during the preceding weekend (P = 0.027) than patients on TZV. Patients on CBV/LPV/r were significantly less satisfied with the convenience of their treatment (P = 0.004) and tended to be less satisfied with the side effects of their treatment (P = 0.091) and continuation of their present treatment (P = 0.056) than patients on TZV. Patients on CBV/LPV/r reported significantly lower levels of role functioning (P = 0.013) than patients on TZV.. In this randomized controlled trial, simplification of therapy to fixed-dose TZV among patients with suppressed HIV RNA was perceived to be more convenient, and resulted in improved adherence and better role functioning, than continuing treatment with CBV/LPV/r.

Topics: Adult; Antiretroviral Therapy, Highly Active; Belgium; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Netherlands; Odds Ratio; Patient Satisfaction; Quality of Life; Ritonavir; Zidovudine

In contrast to resource-rich countries, most HIV-infected patients in resource-limited countries receive treatment without virological monitoring. There are few long-term data, in this setting, on rates of viral suppression or switch to second-line antiretroviral therapy. The DART trial compared clinically driven monitoring (CDM) versus routine laboratory (CD4/haematology/biochemistry) and clinical monitoring (LCM) in HIV-infected adults initiating therapy. There was no virological monitoring in either study group during follow-up, but viral load was measured in Ugandan participants at trial closure. Two thousand three hundred and seventeen (2317) participants from this country initiated antiretroviral therapy with zidovudine/lamivudine plus tenofovir (n = 1717), abacavir (n = 300), or nevirapine (n = 300). Of 1896 (81.8%) participants who were alive and in follow-up at trial closure (median 5.1 years after therapy initiation), 1507 (79.5%) were on first-line and 389 (20.5%) on second-line antiretroviral therapy. The overall switch rate after the first year was 5.6 per 100 person-years; the rate was substantially higher in participants with low baseline CD4 counts (<50 cells/mm3). Among 1207 (80.1%) first-line participants with viral load measured, HIV RNA was <400 copies/ml in 963 (79.8%), 400-999 copies/ml in 37 (3.1%), 1,000-9,999 copies/ml in 110 (9.1%), and ≥10,000 copies/ml in 97 (8.0%). The proportion with HIV RNA <400 copies/ml was slightly lower (difference 7.1%, 95% CI 2.5 to 11.5%) in CDM (76.3%) than in LCM (83.4%). Among 252 (64.8%) second-line participants with viral load measured (median 2.3 years after switch), HIV RNA was <400 copies/ml in 226 (89.7%), with no difference between monitoring strategies. Low switch rates and high, sustained levels of viral suppression are achievable without viral load or CD4 count monitoring in the context of high-quality clinical care.. ISRCTN13968779.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cross-Sectional Studies; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Probability; Retrospective Studies; RNA, Viral; Tenofovir; Uganda; Viral Load; Zidovudine

Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls.. In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression.. Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5-4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5-7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5-3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6-4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01).. In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.

Topics: Anthropometry; Anti-HIV Agents; Child; Child, Preschool; Cross-Sectional Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipid Metabolism; Lipodystrophy; Lipoproteins, HDL; Lipoproteins, LDL; Male; Nevirapine; Stavudine; Triglycerides; Viral Load; Zidovudine

Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials.. We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1).. Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it.. Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.

Topics: Absorptiometry, Photon; Adolescent; Adult; Aged; Aged, 80 and over; Alkynes; Anti-HIV Agents; Benzoxazines; Body Fat Distribution; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Rilpivirine; Tenofovir; Young Adult; Zidovudine

Tenofovir has been associated with a decrease in bone mineral density (BMD). However, data on changes in BMD after discontinuing tenofovir are lacking.. We performed a two-centre randomized pilot study in virologically suppressed HIV-infected patients receiving tenofovir with osteopenia/osteoporosis (OsteoTDF study, ClinicalTrials.gov number NCT 01153217). Fifty-four patients were randomly assigned to switch from tenofovir to abacavir (n = 26) or to continue with tenofovir (n = 28). Changes in lumbar and total hip BMD were evaluated at Week 48 from baseline.. Five patients discontinued the study (three from the tenofovir group and two from the abacavir group). No significant differences were detected between the groups at Week 48 (P = 0.229 for total hip and P = 0.312 for lumbar spine). However, hip BMD improved by 2.1% (95% CI -0.6 to 4.7) (P = 0.043) in the abacavir group and 0.7% (95% CI -0.9 to 2.4) (P = 0.372) in the tenofovir group. Lumbar spine BMD varied by -0.7% (95% CI -3.8 to 3.3) (P ≤ 0.001) in the abacavir group and -1.2% (95% CI -3.8 to 0.4) (P < 0.001) in the tenofovir group.. Switching from tenofovir to abacavir led to a slight improvement in femoral BMD although no differences were detected between groups. Larger studies are necessary before firm recommendations can be made on the discontinuation of tenofovir in patients with a low BMD.

Topics: Adenine; Adult; Anti-HIV Agents; Bone Density; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Osteoporosis; Pilot Projects; Tenofovir; Treatment Outcome

Twice-daily darunavir/ritonavir is indicated in treatment-experienced children (≥3 years). This study assessed once-daily administration in treatment-naïve adolescents.. Phase 2, 48-week, open-label, single-arm study evaluating pharmacokinetics, safety and efficacy of once-daily darunavir/ritonavir 800/100 mg in treatment-naïve, HIV-1-infected adolescents (≥12 to <18 years, ≥40 kg) with zidovudine/lamivudine or abacavir/lamivudine.. Twelve patients (67% female; median 14.4 years) were enrolled. After 24 and 48 weeks, respectively, 11 of 12 (92%) and 10 of 12 (83%) patients achieved viral load <50 copies/mL (intent-to-treat time-to-loss of virologic response); all had ≥1 log10 drop in viral load versus baseline. Median CD4 cell count increased by 175 and 221 cells/mm (intent-to-treat-noncompleter = failure) after 24 and 48 weeks, respectively. Eighty-three percent of patients were adherent to darunavir/ritonavir. One patient was never suppressed and 1 patient rebounded. No patients developed darunavir resistance-associated mutations or lost phenotypic susceptibility to any commercially available protease inhibitor or any background nucleoside reverse transcriptase inhibitor. Eleven patients (92%) reported ≥1 adverse event (AE), considered in 2 patients to be at least possibly related to darunavir (gastrointestinal-related events and dizziness). Four patients had ≥1 serious AE. Three patients reported ≥1 grade 3/4 AE; no serious or grade 3/4 AEs were considered darunavir related. No patients discontinued because of AEs.. Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1-infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Topics: Adolescent; Anemia; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Medication Adherence; Nausea; Neutropenia; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Time Factors; Viral Load; Vomiting; Zidovudine

The anti-HIV drug abacavir is associated with idiosyncratic hypersensitivity reactions and cardiotoxicity. Although the mechanism underlying abacavir-toxicity is not fully understood, drug bioactivation to reactive metabolites may be involved. This work was aimed at identifying abacavir-protein adducts in the hemoglobin of HIV patients as biomarkers of abacavir bioactivation and protein modification. The protocol received prior approval from the Hospital Ethics Committee, patients gave their written informed consent and adherence was controlled through a questionnaire. Abacavir-derived Edman adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method. Abacavir-valine adducts were detected in three out of ten patients. This work represents the first evidence of abacavir-protein adduct formation in humans. The data confirm the ability of abacavir to modify self-proteins and suggest that the molecular mechanism(s) of some abacavir-induced adverse reactions may require bioactivation.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Anti-HIV Agents; Biomarkers; Biotransformation; Dideoxynucleosides; Drug Monitoring; Female; Hemoglobins; HIV Infections; Humans; Male; Middle Aged; Proteins; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

To compare the efficacy and safety of fixed-dose abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) with ritonavir-boosted atazanavir (ATV/r) in treatment-naïve Japanese patients with HIV-1 infection.. A 96-week multicenter, randomized, open-label, parallel group pilot study was conducted. The endpoints were times to virologic failure, safety event and regimen modification.. 109 patients were enrolled and randomly allocated (54 patients received ABC/3TC and 55 patients received TDF/FTC). All randomized subjects were analyzed. The time to virologic failure was not significantly different between the two arms by 96 weeks (HR, 2.09; 95% CI, 0.72-6.13; p=0.178). Both regimens showed favorable viral efficacy, as in the intention-to-treat population, 72.2% (ABC/3TC) and 78.2% (TDF/FTC) of the patients had an HIV-1 viral load <50 copies/mL at 96 weeks. The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms (adverse event: HR 0.66; 95% CI, 0.25-1.75, p=0.407) (regimen modification: HR 1.03; 95% CI, 0.33-3.19, p=0.964). Both regimens were also well-tolerated, as only 11.1% (ABC/3TC) and 10.9% (TDF/FTC) of the patients discontinued the allocated regimen by 96 weeks. Clinically suspected abacavir-associated hypersensitivity reactions occurred in only one (1.9%) patient in the ABC/3TC arm.. Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC, this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients, such as the Japanese population.

Topics: Adenine; Adult; Anti-HIV Agents; Antiviral Agents; Asian People; Atazanavir Sulfate; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Oligopeptides; Organophosphonates; Pilot Projects; Pyridines; Ritonavir; Tenofovir; Treatment Outcome

Topics: Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; Breast Feeding; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Eruptions; Drug Substitution; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Ritonavir; Uganda; World Health Organization

Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group.. Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).

Topics: Adult; Aged; Aged, 80 and over; Anti-Retroviral Agents; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Young Adult

Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available.. Women in the Mma Bana Study initiated HAART from 18 to 34 weeks of gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC) and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum.. Sampling occurred a median of 14 h (range 11-17) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 μg/ml versus 5.51 μg/ml; P = 0.02), antepartum levels with standard LPV dosing were therapeutic for all women (> 1.0 μg/ml). Very low LPV levels (< 0.25 μg/ml) were detected in breast milk. Median ABC levels in breast milk were 85% of those in plasma (0.057 μg/ml versus 0.067 μg/ml). Breast milk concentrations of NVP and 3TC were 27% and 74% of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk.. Standard LPV dosing achieved therapeutic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Botswana; Breast Feeding; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Infant; Lactation; Lamivudine; Lopinavir; Middle Aged; Milk, Human; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Viral Load; Zidovudine

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery.. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007).. Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)].. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Atrophy; Body Composition; Chemistry, Pharmaceutical; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Intention to Treat Analysis; Lamivudine; Lipids; Lipodystrophy; Lopinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure

Improvements in neurocognitive (NC) function have been associated with commencing antiretroviral therapy in HIV-infected subjects. However, the dynamics of such improvements are poorly understood.. We assessed changes in NC function via a validated computerized battery (CogState™, Melbourne, Victoria, Australia) at baseline and after 24 and 48 weeks in a subset of therapy-naïve neuro-asymptomatic HIV-infected subjects, randomized to commence three different antiretroviral regimens.. Of 28 subjects enrolled in the study, nine, eight and 11 were randomly allocated to commence tenofovir/emtricitabine with efavirenz (arm 1), atazanavir/ritonavir (arm 2) and zidovudine/abacavir (arm 3), respectively. Overall improvements in NC function were observed at week 24 and function continued to improve at week 48 (changes in z-score for overall cognitive global score of 0.16 and 0.18 at weeks 24 and 48, respectively). Within the NC speed domains, generally greater improvements were observed in arms 2 and 3, compared with arm 1 (changes in z-score for composite speed scores at weeks 24/48 of 0.16/0.16, -0.29/-0.24 and -0.15/-0.31 in arms 1, 2 and 3, respectively; P = 0.04 for change at week 48 in arm 3 versus arm 1). Finally, improvements in executive function occurred later (only observed at week 48) and were driven by improvements in arm 3 (z-score changes of 0.23, 0.06 and -0.78 in arms 1, 2 and 3, respectively; P = 0.02 for change in arm 3 versus arm 1).. Improvements in NC function continue over the first year after initiating antiretroviral therapy in neuro-asymptomatic HIV-infected subjects.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cognition; Cognition Disorders; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Zidovudine

Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.. HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.. A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.. There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Those receiving tenofovir/emtricitabine (TDF-FTC) had greater bone loss compared with abacavir/lamivudine (ABC-3TC) in a randomized simplification trial (STEAL study). Previous studies associated increased bone turnover and bone loss with initiation of antiretroviral treatment, however it is unclear whether change in bone mineral density (BMD) was a result of specific drugs, from immune reconstitution or from suppression of HIV replication. This analysis determined predictors of BMD change in the hip and spine by dual-energy x-ray absorptiometry in virologically suppressed participants through week 96.. Bone turnover markers (BTMS) tested were: formation [bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP)]; resorption (C-terminal cross-linking telopeptide of type 1 collagen [CTx]); and bone cytokine-signalling (osteoprotegerin, RANK ligand). Independent predictors of BMD change were determined using forward, stepwise, linear regression. BTM changes and fracture risk (FRAX®) at week 96 were compared by t-test. Baseline characteristics (n = 301) were: 98% male, mean age 45 years, current protease-inhibitor (PI) 23%, tenofovir/abacavir-naïve 52%. Independent baseline predictors of greater hip and spine bone loss were TDF-FTC randomisation (p ≤ 0.013), lower fat mass (p-trend ≤ 0.009), lower P1NP (p = 0.015), and higher hip T score/spine BMD (p-trend ≤ 0.006). Baseline PI use was associated with greater spine bone loss (p = 0.004). TDF-FTC increased P1NP and CTx through Wk96 (p<0.01). Early changes in BTM did not predict bone loss at week 96. No significant between-group difference was found in fracture risk.. Tenofovir/emtricitabine treatment, lower bone formation and lower fat mass predicted subsequent bone loss. There was no association between TDF-FTC and fracture risk.

Topics: Absorptiometry, Photon; Adenine; Adult; Bone Density; Bone Remodeling; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir

Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease (CVD) risk, increased HIV disease progression, and death in HIV-infected patients. Use of abacavir has been reported to increase CVD risk. We assessed the effect of virologically suppressive efavirenz (EFV)-based antiretroviral therapy on high sensitivity CRP (hsCRP) levels over a 96-week period with particular attention to the effect of gender and abacavir use. Banked sera from entry and week 96 visits of AIDS Clinical Trials Group A5095 participants were assayed for hsCRP, then analyzed by gender, abacavir randomization, and for correlation with changes in fasting metabolic parameters. Analyses of hsCRP were conducted in two phases and involved a total of 145 men and 51 women. hsCRP did not differ by gender at baseline but higher levels were seen at week 96 in women (median 6 mg/liter; Q1, Q3, 1.8, 13.8) compared to men (median 1.6 mg/liter; Q1, Q3, 0.9, 4.2, p < 0.001), with an estimated shift in hsCRP by gender of 2.5 mg/liter (95% CI 1.0, 5.1). There was no difference in hsCRP levels by abacavir use. Changes in hsCRP did not correlate with changes in insulin resistance or with changes in fasting lipids. Durably virologically suppressive therapy with EFV-based regimens did not decrease hsCRP levels over a 96-week period. hsCRP levels increased significantly only in women. Randomization to abacavir had no effect on changes in hsCRP levels. Changes in hsCRP levels did not correlate with changes in fasting metabolic parameters.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; C-Reactive Protein; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Sex Factors

To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR).. DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR.. The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants.. The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Hypersensitivity; Gene Frequency; Genetic Predisposition to Disease; Genotype; HIV Infections; HLA-B Antigens; Humans; Nevirapine; Uganda

Hypersensitivity reactions are reported in approximately 5% of adults receiving abacavir, but there are few published data in children. Among 1150 African children receiving antiretroviral therapy in a randomized trial, suspected hypersensitivity reactions to abacavir were rare (0.3%; 95% CI, 0.01-0.9). Patients were managed successfully through the provision of clear guidelines and education of clinical staff, children, and their caregivers.

Topics: Adolescent; Africa; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Dideoxynucleosides; Female; HIV Infections; Humans; Hypersensitivity; Incidence; Infant; Male

Abacavir has been associated with an increased risk of acute myocardial infarction, but the pathogenic mechanisms remain unknown. We evaluated longitudinal changes in pro-atherosclerotic biomarkers in patients initiating abacavir or tenofovir.. Consecutive patients initiating antiretroviral therapy (ART) with abacavir/lamivudine or tenofovir/emtricitabine were included. Plasma levels of high sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6), intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (sVCAM-1) and plasminogen activator inhibitor-1 (PAI-1) were measured at baseline and at different time points throughout 48 weeks. Comparisons were adjusted for age, sex, ART status at inclusion, viral load, lipodystrophy, Framingham score and hepatitis C virus co-infection status.. 50 patients were analyzed, 28 initiating abacavir and 22 tenofovir. The endothelial biomarker sVCAM-1 declined significantly in both treatment groups. hsCRP tended to increase soon after starting therapy with abacavir, a trend that was not seen in those initiating tenofovir. IL-6 significantly increased only at week 24 from baseline in patients on abacavir (+225%, p < 0.01) although the differences were not significant between groups. The procoagulant biomarker PAI-1 plasma levels increased from baseline at week 12 (+57%; p = 0.017), week 24 (+72%; p = 0.008), and week 48 (+149%; p < 0.001) in patients on tenofovir, but differences between groups were not statistically significant.. Changes in biomarkers of inflammation, coagulation, and endothelial function are not different in viremic patients starting ART with abacavir/lamivudine or tenofovir/emtricitabine. These changes occur in the early phases of treatment and include anti- and pro-atherosclerotic effects with both drugs.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; C-Reactive Protein; Coagulants; Dideoxynucleosides; Female; HIV Infections; Humans; Inflammation Mediators; Interleukin-6; Longitudinal Studies; Male; Middle Aged; Organophosphonates; Plasminogen Activator Inhibitor 1; Tenofovir; Thrombosis; Vascular Cell Adhesion Molecule-1

Observational and retrospective clinical trial cohorts have reported conflicting results for the association of abacavir use with risk of myocardial infarction (MI), possibly related to issues that may bias estimation of treatment effects, such as time-varying confounders, informative dropout, and cohort loss due to competing events.. We analyzed data from 5056 individuals initiating randomized antiretroviral treatment (ART) in AIDS Clinical Trials Group studies; 1704 started abacavir therapy. An intent-to-treat analysis adjusted for pretreatment covariates and weighting for informative censoring was used to estimate the hazard ratio (HR) of MIs after initiation of a regimen with or without abacavir.. Through 6 years after ART initiation, 36 MI events were observed in 17,404 person-years of follow-up. No evidence of an increased hazard of MI in subjects using abacavir versus no abacavir was seen (over a 1-year period: P=.50; HR, 0.7 [95% confidence interval {CI}, 0.2-2.4]); over a 6-year period: P=.24; HR, 0.6 [95% CI, 0.3-1.4]); these results were robust over as-treated and sensitivity analyses. Although the risk of MI decreased over time, there was no evidence to suggest a time-dependent abacavir effect. Classic cardiovascular disease (CVD) risk factors were the strongest predictors of MI.. We find no evidence to suggest that initial ART containing abacavir increases MI risk over short-term and long-term periods in this population with relatively low MI risk. Traditional CVD risk factors should be the main focus in assessing CVD risk in individuals with human immunodeficiency virus infection.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Risk Assessment

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese.. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline.. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243).. A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96.. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alanine Transaminase; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cholesterol; Cyclopropanes; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Japan; Lamivudine; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

To compare virological effectiveness in patients who continued on a virologically successful first-line boosted protease inhibitor (PI)-containing combination antiretroviral therapy (cART) regimen or who switched to a PI-free cART including efavirenz, nevirapine or abacavir.. From the French Hospital Database on HIV, we selected 439 patients with undetectable viral load (VL) on a first-line boosted PI-containing cART regimen who switched to a PI-free combination including efavirenz, nevirapine or abacavir. Each of these patients was matched with three patients who continued to take their first-line cART regimen, on the basis of gender, age, CD4 cell count, VL, date of cART initiation and the duration of VL undetectability. Time to virological failure (VF) was analysed with Kaplan-Meier curves and Cox models.. The 12 month probabilities of VF were 3.7% and 5.7% in non-switch and switch patients, respectively, and 3.9%, 7.2% and 9.0% in patients switching to efavirenz-, nevirapine- and abacavir-containing cART, respectively. After adjustment, only patients switching to abacavir-containing cART had a higher risk of VF than non-switch patients (adjusted hazard ratio, 1.99; 95% confidence interval, 1.05-3.79).. Switching from a virologically successful first-line boosted PI-containing cART regimen to a non-nucleoside reverse transcriptase inhibitor-containing cART regimen containing either efavirenz or nevirapine is virologically safe, while switching to abacavir-containing cART should be avoided.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nevirapine; Prospective Studies; Treatment Outcome; Viral Load

The aim of this study was to assess changes in the size and cholesterol content of low-density lipoproteins (LDL) and changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC).. This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48.. A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDL-PLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm.. A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients.

Topics: Adenine; Adult; Anti-HIV Agents; Cardiovascular Diseases; Cholesterol, LDL; Clinical Protocols; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipoproteins; Lipoproteins, LDL; Male; Middle Aged; Organophosphonates; Phospholipases A2; Reverse Transcriptase Inhibitors; Tenofovir

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Lamivudine; Nevirapine; RNA, Viral; Viral Load; Zidovudine

Optimal treatment of human immunodeficiency virus (HIV)-associated tuberculosis in patients with high CD4⁺ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression.. We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/μL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4⁺ T-cell counts of < 250 cells/μL, AIDS, or death.. Intervention and comparison arms had similar median CD4⁺ counts (517 and 534 cells/μL, respectively) and HIV RNA levels (4.6 and 4.7 log₁₀ copies/μL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis.. Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4⁺T-cell counts of >350 cells/μL was safe and associated with clinical benefits.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Survival Analysis; Treatment Outcome; Tuberculosis, Pulmonary; Uganda; Young Adult; Zidovudine

AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients.. Primary endpoints were times to virologic failure, regimen modification, and safety event.. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14).. In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Female; HIV; HIV Infections; Humans; Kaplan-Meier Estimate; Lamivudine; Male; Middle Aged; Organophosphonates; RNA, Viral; Tenofovir; Viral Load

Our objective was to evaluate and compare the effect of abacavir on levels of biomarkers associated with cardiovascular risk.. In an open-label randomized trial, HIV-infected patients were randomized 1:1 to switch from zidovudine/lamivudine to abacavir/lamivudine or tenofovir/emtricitabine. In the present analysis, we measured levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin, and myeloperoxidase (MPO) at baseline and 4, 12, and 48 weeks after randomization. D-dimer and fasting lipids were measured at baseline and weeks 12 and 48. Levels of biomarkers at all time points and changes from baseline were compared across study arms using Wilcoxon rank sum test.. Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. Levels of E-selectin (P=0.004) and sVCAM-1 (P=0.041) increased transiently from baseline to week 4 in the abacavir arm compared with the tenofovir arm, but no long-term increases were detected. We found no significant differences between study arms in the levels or changes in the levels of sICAM-1, MPO, d-dimer, IL-6, or hs-CRP. Levels of total cholesterol and high density lipoprotein (HDL) increased in the abacavir arm relative to the tenofovir arm, but no difference was found in total cholesterol/HDL ratio.. In patients randomized to abacavir-based HIV-treatment transient increases were seen in the plasma levels of E-selectin and sVCAM-1 compared with treatment with tenofovir, but no difference between study arms was found in other biomarkers associated with endothelial dysfunction, inflammation, or coagulation. The clinical significance of these findings is uncertain. TRIAL REGESTRATION: Clinicaltrials.gov identifier: NCT00647244.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; Cardiovascular Diseases; Deoxycytidine; Dideoxynucleosides; E-Selectin; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Plasma; Tenofovir; Vascular Cell Adhesion Molecule-1

The aim of this study was to investigate long-term renal function in HIV-infected adults initiating antiretroviral therapy (ART) with a CD4(+) T-cell count < 200 cells/mm³ in Africa.. This was an observational analysis within the DART trial randomizing 3,316 adults to routine laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). Serum creatinine was measured pre-ART (all ≤ 360 μmol/l), at weeks 4 and 12, then every 12 weeks for 4-5 years; estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula. We analysed eGFR changes, and cumulative incidences of eGFR< 30 ml/min/1.73 m² and chronic kidney disease (CKD; <60 ml/min/1.73 m² or 25% decrease if <60 ml/min/1.73 m² pre-ART; confirmed >3 months).. At ART initiation, median CD4(+) T-cell count was 86 cells/mm³; 1,492 (45%) participants had mild (60-< 90 ml/min/1.73 m²), 237 (7%) moderate (30-<60 ml/min/1.73 m² and 7 (0.2%) severe (15-<30 ml/min/1.73 m²) decreases in eGFR. First-line ART was zidovudine/lamivudine plus tenofovir (74%), abacavir (9%) or nevirapine (17%). By 4 years, cumulative incidence of eGFR<30 ml/min/1.73 m² was 2.8% (n=90) and CKD was 5.0% (n=162). Adjusted eGFR increases to 4 years were 1, 9 and 6 ml/min/1.73 m² with tenofovir, abacavir and nevirapine, respectively (P<0.001), and 4 and 2 ml/min/1.73 m² for LCM and CDM, respectively (P=0.005; 2 and 3 ml/min/1.73 m² to 5 years; P=0.81).. On all regimens and monitoring strategies, severe eGFR impairment was infrequent; differences in eGFR changes were small, suggesting that first-line ART, including tenofovir, can be given safely without routine renal function monitoring.

Topics: Adenine; Adult; Africa; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Creatinine; Dideoxynucleosides; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Diseases; Kidney Glomerulus; Lamivudine; Male; Nevirapine; Organophosphonates; Risk Factors; Tenofovir; Time Factors; Zidovudine

We investigated virological response and the emergence of resistance in the Nevirapine or Abacavir (NORA) substudy of the Development of Antiretroviral Treatment in Africa (DART) trial.. Six hundred symptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected adults (CD4 cell count, <200 cells/mm(3)) from 2 Ugandan centers were randomized to receive zidovudine-lamivudine plus abacavir or nevirapine. Virology was performed retrospectively on stored plasma samples at selected time points. In patients with HIV RNA levels >1000 copies/mL, the residual activity of therapy was calculated as the reduction in HIV RNA level, compared with baseline.. Overall, HIV RNA levels were lower in the nevirapine group than in the abacavir group at 24 and 48 weeks (P < .001), although no differences were observed at weeks 4 and 12. Virological responses were similar in the 2 treatment groups for baseline HIV RNA level <100,000 copies/mL. The mean residual activity at week 48 was higher for abacavir in the presence of the typically observed resistance pattern of thymidine analogue mutations (TAMs) and M184V (1.47 log(10) copies/mL) than for nevirapine with M184V and nonnucleoside reverse-transcriptase inhibitor mutations, whether accompanied by TAMs (0.96 log(10) copies/mL) or not (1.18 log(10) copies/mL).. There was more extensive genotypic resistance in both treatment groups than is generally seen in resource-rich settings. However, significant residual activity was observed among patients with virological failure, particularly those receiving zidovudine-lamivudine plus abacavir.

Topics: Adult; Anti-Retroviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; Humans; Kaplan-Meier Estimate; Lamivudine; Male; Mutation; Nevirapine; RNA, Viral; Uganda; Viral Load; Zidovudine

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779.. Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases).. ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment.. UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Topics: Adenine; Adolescent; Adult; Africa; Aged; Anemia; Anti-Retroviral Agents; CD4 Lymphocyte Count; Creatinine; Dideoxynucleosides; Disease Progression; Drug Monitoring; Female; Glomerular Filtration Rate; Hemoglobins; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Male; Middle Aged; Neutropenia; Neutrophils; Nevirapine; Organophosphonates; RNA, Viral; Tenofovir; Urea; Viral Load; Zidovudine

To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers.. Sub-study of the BICOMBO study in which participants were randomized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine.. We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up.. Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. -6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. -9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (-3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. -2.8%), IL-6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. -0.01%), selectin E (-0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (-2.5 vs. 8.8%), adiponectin (-2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P > or = 0.12 for all comparisons).. Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; Cardiovascular Diseases; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipids; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome; Viral Load

To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF).. This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined.. Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (-0.15 log10 per day vs. -0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/10 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/10 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (rho = -0.529; P = 0.045).. In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

Topics: Adenine; Adult; Anti-HIV Agents; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; RNA, Viral; Tenofovir; Treatment Outcome

Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa.. A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat.. The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001).. The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Topics: Adult; Body Weight; CD4 Lymphocyte Count; Dideoxynucleosides; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Medication Adherence; Middle Aged; Nevirapine; Recurrence; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Uganda; Viral Load; Zidovudine

Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells.. A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays.. No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus.. An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; Drug Administration Schedule; Female; HIV; HIV Infections; Humans; Lamivudine; Male; Mitochondria; Organophosphonates; Reverse Transcriptase Inhibitors; RNA; RNA, Mitochondrial; Tenofovir

Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Young Adult; Zidovudine

Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3-<36 months.. Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration-time curve over 24 h (AUC(0-24)) and the maximum concentration (C(max)) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80-1.25 were considered bioequivalent.. A total of 18 children (4, 6 and 8 in the 3-<12, 12-<24 and 24-<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC(0-24), once-daily versus twice-daily, was 1.07 (90% CI 0.92-1.23) for abacavir and 0.91 (90% CI 0.79-1.06) for lamivudine. C(max) almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73-2.42) and 1.78 (90% CI 1.52-2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively.. Bioequivalence was demonstrated on AUC(0-24) between twice-daily and once-daily abacavir; very similar AUC(0-24) values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3-<36 months.

Topics: Anti-HIV Agents; Child, Preschool; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Treatment simplification strategies involving induction with a ritonavir (RTV)-boosted (/r) protease inhibitor regimen followed by simplification (without RTV) are appealing because they may offer sustained virologic suppression while minimizing potential long-term adverse effects associated with RTV.. This open-label, randomized, noninferiority study enrolled 515 antiretroviral therapy-naive patients to receive abacavir/lamivudine plus atazanavir/RTV (ATV/r) followed by randomization at week 36 (N = 419) to maintain or discontinue RTV for an additional 48 weeks. Eligibility for randomization required confirmed HIV RNA level below 50 copies/ml and no virologic failure. Protocol-defined virologic failure after week 36 was confirmed rebound of HIV RNA level at least 400 copies/ml. The primary endpoint was the proportion of patients with HIV RNA level below 50 copies/ml at week 84 (time to loss of virologic response). This study is registered with ClinicalTrials.gov number NCT00440947.. At week 84, noninferiority of ATV to ATV/r (95% confidence interval around the treatment difference -1.75 to 12.48%) was demonstrated with 181 of 210 (86%) patients in the ATV group and 169 of 209 (81%) in the ATV/r group maintaining HIV RNA level below 50 copies/ml. During the randomized phase (weeks 36-84), 10 versus 14% of patients in the ATV and ATV/r arms, respectively, experienced a drug-related grades 2-4 adverse event with hyperbilirubinemia being the most frequently reported (4 versus 10%). The overall rate of protocol-defined virologic failure was 2%; no patient had virus that developed a major protease inhibitor mutation.. ATV in combination with abacavir/lamivudine is a potent and well tolerated regimen in patients who have achieved initial suppression on an induction regimen and represents a viable treatment simplification strategy.

Topics: Adult; Aged; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome; Viral Load; Young Adult

Antiretroviral therapy is complicated by drug interactions and contraindications. Novel regimens are needed.. This open label study randomly assigned treatment-naive, human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz (Arm I), with ritonavir-boosted atazanavir (Arm II), or with zidovudine/abacavir (Arm III). Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis. Treatment arms were noninferior if the upper limit of the 95% confidence interval (CI) was <0.5 log(10) copies/mL. Secondary objectives included virologic, immunologic and safety end points.. The intention-to-treat population comprised 322 patients (Arm I, n = 114; Arm II, n = 105; and Arm III, n = 103). Noninferiority for the primary end point was established. Analysis for superiority showed that Arm III was significantly less potent than Arm I (-0.20 log(10) copies/mL; 95% CI, -0.39 to -0.01 log(10) copies/mL; P = .038). The proportions of patients on each of Arm I (95%) and Arm II (96%) with <200 copies/mL were not different (P = .75), but the percentage of patients in Arm III with <200 copies/mL (82%) was significantly lower (P = .005). CD4+ cell counts did not differ. Serious adverse events were more frequent in Arm III (n = 30) than in Arm I or Arm II (n = 15 for each; P = .062).. A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication, compared with the suppression demonstrated by standard antiretroviral therapy regimens, although it did meet the predetermined formal definition of noninferiority. Secondary analyses indicated statistically inferior virologic and safety performance. Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Pyridines; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

The Simplification of antiretroviral therapy with Tenofovir-Emtricitabine or Abacavir-Lamivudine trial (STEAL) study randomized HIV participants to switch existing nucleoside reverse transcriptase inhibitors (NRTI) to either abacavir/lamivudine (ABC/3TC; n = 179) or tenofovir/emtricitabine (TDF/FTC; n = 178). An increased risk in cardiovascular disease (CVD) was reported (hazard ratio 7.7, P = 0.048) in ABC/3TC recipients compared with TDF/FTC in the STEAL study. The impact of ABC/3TC treatment on a range of CVD and inflammatory biomarkers was explored.. Biomarkers were assessed at 0, 12, 24, and 48 weeks to examine: inflammation - high sensitive C-reactive protein, amyloid-P, amyloid-A, interleukin 6, interleukin 10, interferon α, and macrophage migration inhibitory factor; coagulation - D-dimer and fibrinogen; platelet function - soluble P-selectin; endothelial function - vascular cell adhesion molecule 1 and intercellular adhesion molecule 1; renal function - cystatin C. The primary endpoint was the difference between arms for mean change from baseline to week 12. Secondary analyses were differences between groups for mean change from baseline to weeks 24 and 48, time-weighted change from baseline to week 48, and changes to week 12 stratified by Framingham CVD risk score at baseline.. Sera were available from 330 (92%) of 357 participants. At baseline, all biomarkers were similar between treatment arms and when stratified for baseline NRTI exposure. There were no significant differences between treatment arms in the mean change from baseline to week 12 for any biomarkers. No consistent between-group differences were seen in the secondary analyses that could suggest one pathophysiological pathway.. A thorough examination of selected biomarkers associated with cardiovascular morbidity and mortality did not reveal associations with the use of ABC/3TC relative to use of TDF/FTC.

Topics: Biomarkers; Cardiovascular Diseases; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Viral Load

No data on once-daily dosing of nucleoside analogues in African children currently exist. We compared the pharmacokinetics (PK) of once- versus twice-daily lamivudine and abacavir treatment using the World Health Organization recommended weight band dosing of scored adult tablets.. HIV type-1 (HIV-1)-infected Ugandan children aged 3-12 years receiving antiretroviral therapy that included lamivudine and abacavir twice daily (total 150+300 mg, 225+450 mg and 225/300+600 mg daily for 12-<20, 20-<25 and ≥25 kg, respectively) were enrolled in a crossover study. Plasma PK sampling (at 0, 1, 2, 4, 6, 8 and 12 h after observed morning intake) was performed for the twice-daily regimen at steady-state. Children were then switched to once-daily treatment with PK sampling repeated 4 weeks later (with an additional 24 h sample). Acceptability questionnaires were completed at both time points. Daily area under the curve (AUC(0-24)) and maximum concentrations (C(max)) were compared by geometric mean ratios (GMRs).. A total of 41 HIV-1-infected children (median age of 7 years) and n=23, n=14 and n=4 in 12-<20, 20-<25 and ≥25 kg weight bands, respectively, were enrolled. Mean AUC(0-24) was 13.0 and 12.0 mg•h/l for once- and twice-daily lamivudine (GMR 1.09, 90% confidence intervals [CI] 0.98-1.20) and 15.3 and 15.6 mg•h/l for once- and twice-daily abacavir (GMR 0.98, 90% CI 0.89-1.08), respectively, with no difference in 3-6 versus 7-12 year olds. C(max) was 76% (lamivudine) and 64% (abacavir) higher on once-daily regimens. For both children and caregivers, once-daily dosing of lamivudine plus abacavir was highly acceptable and strongly preferred over twice-daily.. In children aged 3-12 years, AUC(0-24) of lamivudine and abacavir were bioequivalent on once- and twice-daily regimens. Once-daily dosing of abacavir and lamivudine could provide an alternative dosing strategy for HIV-1-infected children, with high acceptability and strong preference suggesting the potential for improved adherence.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Child; Child, Preschool; Confidence Intervals; Cross-Over Studies; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Uganda

Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days -1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC(0-24)) and comparable CBV-TP concentrations at the end of the dosing interval (C(tau)). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C(max)) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC(0-24) and 99% higher CBV-TP C(max) than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC(0-24) and 81% higher weight-adjusted CBV-TP AUC(0-24) than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C(tau) values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

Topics: Adult; Aged; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Middle Aged

Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC(0-4)), the maximum concentration of the drug (C(max)), and the residual concentration of the drug at the end of the dosing interval (C(trough)) for plasma and the AUC(0-4) and C(trough) for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC(0-4) was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C(trough) values for women.

Topics: Adenine; Adult; Anti-HIV Agents; Area Under Curve; Cross-Sectional Studies; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Middle Aged; Organophosphonates; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

Abacavir (ABC) oral clearance, adjusted for body size, is approximately 2 times higher for children than adults with a corresponding difference in dose regimens. However, there are limited data available in the adolescent population. The pharmacokinetics (PKs) of ABC and primary metabolites were determined in HIV-1-infected children and adolescents to evaluate age and patient characteristics as a basis for adjusting ABC dose regimens and to assess the influence of metabolite formation on PK parameters.. Pediatric subjects 9-18 years of age receiving antiretroviral therapy for HIV-1 infection were stratified by Tanner stage and given a single 8 mg/kg dose of ABC oral solution. Blood samples (n = 10) were obtained over 8 hours and measured for ABC, glucuronide, and carboxylate metabolites using high-performance liquid chromatography. PK parameters for children (Tanner stages 1-2; TS1) and adolescents (Tanner stages 3-5; TS2) were compared.. Twenty-five subjects were enrolled. ABC mean (range) maximum concentration (Cmax; microg/mL), area under the curve (microg.hr/mL), half-life (hours), and apparent clearance (CL/F; mL/min per kg) for TS1 and TS2 were 3.5 (1.2-5.6) vs 3.4 (1.8-5.9), 8.0 (2.1-18.6) vs 8.9 (3.1-17.2), 1.3 (0.7-2.5) vs 1.4 (0.9-1.9), and 22.1 (7.0-59.2) vs 18.4 (7.7-42.9) and not significantly different. Age, Tanner stage, and sex were not correlated with ABC clearance by univariate analysis. The ratios of metabolites to ABC area under the curve were correlated with ABC clearance as were the ratios of metabolites to ABC concentrations at the 6-hour time point.. ABC oral clearance in HIV-1-infected pediatric patients does not change during puberty, is similar to younger children, and is higher than previously published in adults. Therefore, dosing adolescents as adults should be reexamined. Intersubject PK variability is substantial and is not correlated with body size or age but more likely due to differences in metabolite formation that may be genetic in origin.

Topics: Administration, Oral; Adolescent; Age Factors; Anti-HIV Agents; Child; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Metabolic Clearance Rate

Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches.. Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48.. Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm.. Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Intra-Abdominal Fat; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Radiography, Abdominal; Stavudine; Thigh; Viral Load; Zidovudine

The long-term efficacy of once-daily (qd) fosamprenavir (FPV) 1400 mg boosted by ritonavir 100 mg (FPV/r100) has not been evaluated previously. A 96-week open-label, randomized, multicenter study compared the efficacy/safety of FPV/r100 with FPV 1400 mg boosted by ritonavir 200 mg qd (FPV/r200), plus abacavir/lamivudine 600 mg/300 mg qd, in antiretroviral-naive, HIV-infected patients with viral load (VL)> or =1000 copies/ml. Primary endpoints were proportion of patients achieving VL <400 copies/ml or discontinuing for drug-related reasons. In the intent-to-treat:exposed (ITT-E) population, missing = failure (M = F), and observed approaches were used to assess between-arm differences in VL responses by Cochran-Mantel-Haenszel test and CD4(+) count by Wilcoxon rank-sum test. One hundred and fifteen (115) patients enrolled, with 58 on FPV/r100 (median VL 4.7 log(10) copies/ml; CD4(+) count 259 cells/mm(3)) and 57 on FPV/r200 (median VL 4.9 log(10) copies/ml; CD4(+) count 179 cells/mm(3)). Fewer FPV/r100-treated patients discontinued treatment prematurely (12 vs. 24) and experienced virologic failure (5 vs. 8, none developing major protease inhibitor resistance mutations). At week 96, more FPV/r100-treated patients had VL <400 copies/ml [ITT-E,M = F: 78% (45/58) vs. 53% (30/57), p = 0.006; observed: 98% (45/46) vs. 94% (30/32)] and VL<50 copies/ml [ITT-E,M = F: 66% (38/58) vs. 53% (30/57); observed: 83% (38/46) vs. 94% (30/32)]. The FPV/r100 and FPV/r200 arms were similar at week 96 regarding median change from baseline in CD4(+) count (+265 vs. +260 cells/mm(3)) and total cholesterol (+33 vs. +35 mg/dl), and in total-cholesterol:HDL-cholesterol ratio (4.0 vs. 4.1) and type/frequency of treatment-related grade 2-4 adverse events, although FPV/r100 was associated with a lower elevation in triglycerides (+27 vs. +48 mg/dl). In conclusion, through 96 weeks, FPV/r100 was more effective and prompted less elevation in triglycerides than FPV/r200.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression.. We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure ["switching = failure" intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function.. Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval -2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group.. In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Topics: Adenine; Adult; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Spain; Tenofovir; Treatment Failure; Treatment Outcome

Thymidine nucleoside reverse transcriptase inhibitors (NRTIs) are associated with subcutaneous fat loss. Facial changes cannot be assessed by dual-energy X-ray absorptiometry (DEXA) scans. There are limited objective data on the reversibility of facial lipoatrophy.. We performed a facial volume substudy of a randomized thymidine NRTI replacement study carried out in HIV-infected subjects with moderate to severe lipoatrophy. Facial volume changes were assessed using validated 3D laser imaging. Changes in body composition were measured using DEXA scans. The association between changes in facial volume and body composition parameters at 48 weeks was measured using Spearman's rank correlation.. Forty-seven individuals (46 male), 11 receiving zidovudine and 36 receiving stavudine, switched to either tenofovir disoproxil fumarate (DF) (n=23) or abacavir (ABC) (n=24). Thirty-nine of these 47 patients (84.8%) reported facial lipoatrophy at baseline. The median volume increase in both cheeks from baseline was 1857.3 mm(3). These volume changes and increases in limb fat at 48 weeks were similar in the two groups and correlated significantly (Spearman's r=0.41, P=0.004).. Facial volume in lipoatrophic individuals was found to increase after thymidine NRTI replacement. We demonstrated a significant correlation between improvements in facial and limb fat parameters. Switching from thymidine NRTIs in patients with facial lipoatrophy could potentially reduce the need for cosmetic interventions.

Topics: Absorptiometry, Photon; Adenine; Adult; Aged; Body Composition; Cheek; Dideoxynucleosides; Female; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Middle Aged; Organophosphonates; Quality of Life; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine

Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients.. Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks.. At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups.. Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNA > or = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNA > or = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNA > or = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.

Topics: Adenine; Adult; Amino Acid Substitution; Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Pilot Projects; RNA, Viral; Tenofovir; Treatment Failure; Zidovudine

The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)-infected patients.. Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for > or =6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1-(13)C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13+/-4% (P=0.01) and 16+/-6% (P=0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17+/-7% (P=0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed.. NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Apolipoprotein A-I; Cholesterol, HDL; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Kinetics; London; Magnetic Resonance Spectroscopy; Male; Middle Aged; Netherlands; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Up-Regulation; Viral Load

To assess the potency, efficacy and toxicity of abacavir/lamivudine (ABC/3TC) versus tenfovir/emcitrabine (TDF/FTC) with efavirenz (EFV) in naive patients with HIV infection a prospective observational study was carried out to evaluate immunovirological parameters every three months and metabolic parameters every six months. In all, 21 patients were enrolled (10 on ABC/3TC and 11 on TDF/FTC). Fisher's test revealed no statistically significant difference between the two arms in terms of immunological recovery and control of viral replication. For metabolic parameters at week 48 no statistically significant differences were noted between the two arms. The two ABC/3TC and TDF/FTC backbones showed the same potency; ABC had a more negative impact on metabolic parameters without statistical power.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Hyperinsulinism; Hyperlipidemias; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Prospective Studies; Tenofovir; Thymidine; Treatment Outcome; Young Adult

Fixed dose combination abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) among HIV-1 and tuberculosis (TB)-coinfected patients was evaluated and outcomes between early vs. delayed initiation were compared. In a randomized, pilot study conducted in the Kilimanjaro Region of Tanzania, HIV-infected inpatients with smear-positive TB and total lymphocyte count <1200/mm(3) were randomized to initiate ABC/3TC/ZDV either 2 (early) or 8 (delayed) weeks after commencing antituberculosis therapy and were followed for 104 weeks. Of 94 patients screened, 70 enrolled (41% female, median CD4 count 103 cells/mm(3)), and 33 in each group completed 104 weeks. Two deaths and 12 serious adverse events (SAEs) were observed in the early arm vs. one death, one clinical failure, and seven SAEs in the delayed arm (p = 0.6012 for time to first grade 3/4 event, SAE, or death). CD4 cell increases were +331 and +328 cells/mm(3), respectively. TB-immune reconstitution inflammatory syndromes (TB-IRIS) were not observed in any subject. Using intent-to-treat (ITT), missing = failure analyses, 74% (26/35) vs. 89% (31/35) randomized to early vs. delayed therapy had HIV RNA levels <400 copies/ml at 104 weeks (p = 0.2182) and 66% (23/35) vs. 74% (26/35), respectively, had HIV RNA levels <50 copies/ml (p = 0.6026). In an analysis in which switches from ABC/3TC/ZDV = failure, those receiving early therapy were less likely to be suppressed to <400 copies/ml [60% (21/35) vs. 86% (30/35), p = 0.030]. TB-IRIS was not observed among the 70 coinfected subjects beginning antiretroviral treatment. ABC/3TC/ZDV was well tolerated and resulted in steady immunologic improvement. Rates of virologic suppression were similar between early and delayed treatment strategies with triple nucleoside regimens when substitutions were allowed.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Male; Pilot Projects; Tanzania; Tuberculosis; Viral Load; Zidovudine

Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa) qd to achieve a qd regimen.. A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd.. Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7-100%) vs. 96.6% (60.0-100%) (P=0.017); dosing compliance 97.1% (64.3-100%) vs. 91.9% (33.3-100%) (P=0.016); and timing compliance 95.5% (53.8-100%) vs. 86.3% (4.3-100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82-99%) vs. 85% (75-93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC.. Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chi-Square Distribution; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Patient Compliance; Patient Satisfaction; Reverse Transcriptase Inhibitors; Statistics, Nonparametric; Viral Load

A hypersensitivity reaction is associated with abacavir in approximately 2-8% of exposed patients. The frequency of the HLA-B*5701 allele varies across racial groups and significantly correlates with risk of hypersensitivity. Studies in Europe and Western Australia demonstrated that prospective screening can significantly reduce the rate of hypersensitivity by avoiding the use of abacavir in patients carrying the HLA-B*5701 allele. Prospective HLA-B*5701 screening in a large, racially diverse North American population resulted in less than 1% of individuals diagnosed with a suspected abacavir hypersensitivity reaction (ABC HSR) and no positive skin patch test through 30 weeks among HLA-B*5701-negative individuals.

Topics: Adult; Alleles; Anti-Retroviral Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; North America

We evaluated a single-class quadruple nucleoside/nucleotide regimen in a 96-week prospective one-arm pilot study in adult HIV-infected naive patients with CD4 >100 cells/microl. Standard zidovudine/lamivudine/abacavir and tenofovir doses were given. Virologic efficacy was evaluated by intent-to-treat (ITT), switch = failure and on-treatment (OT) analyses. A total of 54 patients were included (median CD4 count 254 cells/microl, VL 79,706 copies/ml). A median drop in VL of 2 log at 14 days and >3 log since week 12 was observed. A total of 34/54 (63%) patients (ITT) and 34/39 (87%) patients (OT) had VL <50 copies/ml at 96 weeks. Four (7%) patients switched therapy due to adverse events, 5 (9%) had virologic failure, and 1 died. Similar efficacy results were observed irrespective of baseline VL (> or <5 log) or CD4 cells (> or <250/microl). A median CD4 gain of +223 cells/microl was achieved. K65R + 41L + 219Q were detected in one patient at virologic failure. Only two patients presented fat loss on clinical evaluation. A decrease in total cholesterol (p = 0.007) and LDLc (p = 0.016) was observed. Our data suggest that zidovudine/lamivudine/abacavir plus tenofovir is a simple, effective, and well-tolerated NNRTI/PI-sparing regimen, even for patients with high viral loads. Larger trials comparing this option with standard initial antiretroviral regimens should be conducted.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Endpoint Determination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Pilot Projects; Prospective Studies; Spain; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

The aim of the PREDICT-1 study was to determine the clinical utility of the pharmacogenetic test identifying HLA-B*5701 to reduce the incidence of hypersensitivity reaction to abacavir, diagnosed clinically and with immunological confirmation, as well as to reduce unwarranted withdrawal of this drug. In the PREDICT-1 study, 1,956 patients were randomized to be screened for HLA-B*5701 before starting abacavir treatment (excluding participants who were HLA-B*5701-positive) or to receive abacavir without knowing their HLA-B*5701 status under conventional clinical monitoring. The prevalence of HLA-B*5701-positivity was 5.7%. In the group that underwent prospective screening, no hypersensitivity tests with immunological confirmation (by positive epicutaneous patch testing) were observed compared with an incidence of 2.7% in the group undergoing standard follow-up. The sensitivity of prospective screening in predicting immunologically confirmed hypersensitivity reaction to abacavir was 100% and its negative predictive value was 100%. The number of clinically suspected hypersensitivity reactions to abacavir was also lower in the screened group (3.4% versus 7.8% in the group undergoing conventional follow-up). The sensitivity of epicutaneous patch testing for immunological confirmation was 100%.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Mass Screening; Pharmacogenetics; Prospective Studies; Sensitivity and Specificity

Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs)--abacavir and didanosine--may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought.. Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N = 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.. Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n = 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n = 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n = 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P = 0.02) and 16% (P = 0.02) higher for patients receiving abacavir (N = 175) compared with those receiving other NRTIs (N = 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers.. Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event.

Topics: Adult; Anti-Retroviral Agents; Biomarkers; C-Reactive Protein; Didanosine; Dideoxynucleosides; Electrocardiography; Female; HIV Infections; HIV-1; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk; Serum Amyloid A Protein; Serum Amyloid P-Component

To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine.. A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared.. In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day.. HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Topics: Adenine; Adult; Anti-HIV Agents; Blood; Cohort Studies; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; Follow-Up Studies; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Male; Middle Aged; Multivariate Analysis; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Tenofovir; Treatment Outcome; Viral Load

Topics: Adenine; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir

Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir.. This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir.. The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001).. HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)

Topics: Adolescent; Adult; Aged; Dideoxynucleosides; Double-Blind Method; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Patch Tests; Reverse Transcriptase Inhibitors

The recent introduction of novel, fixed nucleoside-nucleotide reverse transcriptase inhibitor (NRTI) combinations (tenofovir-emtricitabine, and abacavir-lamivudine) expanded the spectrum of available formulations and concurrently increased patients' adherence levels. A prospective survey of the open-label use of these two fixed combinations was performed in 158 patients belonging to our single-center cohort of more than 1,000 HIV-infected subjects enrolled in the last 18 months, and followed for at least 12 months. During the last 18 months, 95 consecutive, evaluable patients (60.1%) received for the first time tenofovir-emtricitabine, or abacavir-lamivudine (63 patients, 39.9%), and were followed for at least 12 months with periodic clinical and laboratory examinations. Among the 53 evaluable patients who were naïve to all antiretrovirals, tenofovir-emtricitabine has been given to 42 subjects (79.2%), mostly associated with efavirenz (26 cases), or different boosted protease inhibitors (16 subjects), whereas abacavir-lamivudine was administered to 11 patients (in 10 cases of 11, together with boosted protease inhibitors). In the remaining 105 patients, tenofovir-emtricitabine or abacavir-lamivudine therapy represented a switch from a prior combination antiretroviral regimen, and was predominantly associated with boosted protease inhibitors (61 patients), versus efavirenz or nevirapine (26 cases), or other drug combinations containing protease inhibitors (the remaining 18 patients). Among the 105 pretreated patients, the prescription of tenofovir-emtricitabine (53 patients) was as frequent as that of abacavir-lamivudine (52 cases), and the therapeutic change was primarily prompted by toxicity or poor tolerability (59 patients), followed by therapeutic failure and viral resistance (46 cases as a whole), and always encompassed a regimen simplification also. Both fixed combinations were well tolerated, and an adherence rate more than 90% was estimated among evaluable patients. From a tolerability point of view, the emtricitabine-tenofovir association was never withdrawn due to untoward events, while only two cases of early abacavir-lamivudine suspension occurred, due to a probable abacavir hypersensitivity reaction. From our preliminary experience, a major role seems to be played by tenofovir-emtricitabine in first-line treatments (preferably among "compact" regimens based on efavirenz), while the proportionally increased abacavir-lamivudine prescription to

Topics: Adenine; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load

To compare the safety/tolerability of abacavir and nevirapine in HIV-infected adults starting antiretroviral (ARV) therapy in Uganda.. Twenty-four-week randomized double-blind trial conducted with 600 symptomatic ARV-naive adults with CD4 <200 cells/mm(3) allocated to zidovudine/lamivudine plus 300 mg abacavir (A) and nevirapine placebo (n = 300) or 200 mg nevirapine (N) and abacavir placebo (n = 300) twice daily. The primary endpoint was any serious adverse event (SAE) definitely/probably or uncertain whether related to blinded nevirapine/abacavir. Secondary endpoints were adverse events leading to permanent discontinuation of blinded nevirapine/abacavir, and grade 4 events.. Seventy-two per cent participants were women; 19% had WHO stage 4 disease; the median age was 37 years (range 18-66); the median baseline CD4 count was 99 cells/mm(3) (1-199). Ninety-five per cent completed 24 weeks: 4% died and 1% were lost to follow-up. Thirty-seven SAEs occurred on blinded drug in 36 participants. Twenty events [6 (2.0%) abacavir, 14 (4.7%) nevirapine participants] were considered serious adverse reactions definitely/probably/uncertain whether related to blinded abacavir/nevirapine [HR = 0.42 (95% CI 0.16-1.09) P = 0.06]. Only 2.0% of abacavir participants [six patients (0.7-4.3%)] experienced a suspected hypersensitivity reaction (HSR). In total 14 (4.7%) abacavir and 30 (10.0%) nevirapine participants discontinued blinded abacavir/nevirapine (P = 0.02): because of toxicity (6A, 15N; P = 0.07, all rash/possible HSR and/or hepatotoxicity), anti-tuberculosis therapy (6A, 13N), or for other reasons (2A, 2N).. There was a trend towards a lower rate of serious adverse reactions in Ugandan adults with low CD4 starting ARV regimens with abacavir than with nevirapine. This suggests that abacavir could be used more widely in resource-limited settings without major safety concerns.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Treatment Outcome; Uganda; Zidovudine

To assess long-term changes in subcutaneous tissue among antiretroviral-naive persons initiating 1 of 3 nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens.. We compared changes in 308 participants initiating stavudine plus lamivudine (d4T+3TC; N = 63), zidovudine plus lamivudine (ZDV+3TC; N = 192), and abacavir plus lamivudine (ABC+3TC; N = 53), along with protease inhibitors and/or non-NRTIs. Anthropometric measurements (skinfolds) were performed at baseline and 4-month intervals. Rates of change (mm/y) over 36 months, for the early period (months 4 through 12) and late period (months 16 through 36), were calculated.. The rates were negative (tissue loss) for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds. For ABC+3TC, most rates were positive (tissue gain). No differences among regimens were seen for the rates of change in the subscapular or suprascapular skinfolds. Rates in the early period were generally positive. The late period rates were negative for d4T+3TC and ZDV+3TC and significantly different from 0 for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds, whereas ABC+3TC had less loss in the late period. Most early versus late differences were significant for d4T+3TC and ZDV+3TC; only the triceps skinfold was significant for ABC+3TC.. In this prospective nonrandomized evaluation, subcutaneous tissue changes varied by regimen. Similar losses were demonstrated for d4T+3TC and ZDV+3TC, whereas ABC+3TC had gains. Temporal differences in rates for d4T+3TC and ZDV+3TC suggest initial recovery followed by long-term treatment effect.

Topics: Adult; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Subcutaneous Fat; Zidovudine

To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients.. This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks.. A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (-1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed.. Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Extremities; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lipid Metabolism; Lipids; Male; Middle Aged; Oxazines; Stavudine; Viral Load

To assess metabolic changes after initiation of protease inhibitor (PI)-sparing regimens in antiretroviral-naive patients.. Metabolic changes were analyzed within the triple-nucleoside (zidovudine [ZDV]/lamivudine [3TC]/abacavir [ABC])-containing, 3-drug efavirenz (EFV) [ZDV/3TC + EFV]-containing, and 4-drug EFV [ZDV/3TC/ABC + EFV]-containing arms of the AIDS Clinical Trials Group multicenter trial A5095. Metabolic values were compared with published US general population norms.. From week 0 to week 24, all arms exhibited similar mild median increases in glucose and decreases in insulin sensitivity, whereas changes in lipids were greater in the ZDV/3TC + EFV and ZDV/3TC/ABC + EFV arms than in the ZDV/3TC/ABC arm: triglyceride (TG; 7, 18, and -1 mg/dL, respectively), total cholesterol (TC; 23, 28, and 5 mg/dL, respectively), low-density lipoprotein cholesterol (LDL-C; 9, 14, and 1 mg/dL, respectively), and high-density lipoprotein cholesterol (HDL-C; 10, 10, and 5 mg/dL, respectively). Adjusted mean study lipid values of all study participants at week 0 and week 96 compared with those of the National Health and Nutrition Examination Survey (NHANES) 1999 through 2002 values were: TG (148, 187, and 123 mg/dL, respectively), TC (164, 195, and 203 mg/dL, respectively), HDL-C (35, 47, and 51 mg/dL, respectively), and LDL-C (101, 117, and 123 mg/dL, respectively) (P < or = 0.005 for each value vs. NHANES values).. Similar mild increases in glucose and decreases in insulin sensitivity were observed in all regimens, whereas lipids were modestly higher in the EFV-containing arms. Compared with general population norms, the metabolic dysfunctions of concern after these PI-sparing therapies were increasingly abnormal TC and lower (but improved relative to baseline) HDL-C levels.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Glucose; Body Composition; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Insulin Resistance; Lactic Acid; Lamivudine; Lipids; Male; Reverse Transcriptase Inhibitors; Zidovudine

Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.

Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Treatment Outcome

We sought to compare clearance rates of plasma human immunodeficiency virus type 1 (HIV-1) RNA in men and women starting triple-nucleoside-based versus efavirenz (EFV)-based regimens.. First- and second-phase decay rates of plasma HIV-1 were compared in men and women initiating a triple nucleoside reverse-transcriptase inhibitor (NRTI) regimen versus regimens that included EFV plus an NRTI. Subjects (n=64) were randomized to receive zidovudine/lamivudine/abacavir (triple-nucleoside regimen), zidovudine/lamivudine plus EFV (3-drug EFV regimen) or zidovudine/lamivudine/abacavir plus EFV (4-drug EFV regimen). Plasma HIV-1 RNA levels were fitted to a biexponential viral-dynamics model using a nonlinear mixed-effects model. Nonparametric Wilcoxon tests compared empirical Bayes estimates of first- and second-phase viral decay rates between treatment arms and sex.. Median first-phase viral decay rates were significantly faster in subjects receiving the 3-drug EFV regimen (0.67/day), compared with those receiving the triple-nucleoside regimen (0.56/day; P=.02). The second-phase viral decay rate was also faster in the 3-drug EFV group than in the triple-nucleoside group (P=.09). Decay rates in the 4-drug EFV group were intermediate. Viral decay rates were not significantly different in men and women. CONCLUSIONS Faster initial viral decay in subjects randomized to a 3-drug EFV-based regimen corresponded to the overall superior efficacy of that regimen. Viral decay rates did not differ by sex.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Prospective Studies; Regression Analysis; RNA, Viral; Time Factors; Zidovudine

The K70E mutation in HIV-1 reverse transcriptase was observed in 10% of virologic non-responders of the abacavir/lamivudine/tenofovir arm of ESS30009, alone, or in mixtures with K65R by population sequencing. Clonal analysis of six ESS30009 K70E isolates failed to identify double mutants carrying K65R+K70E. Site-directed K70E mutants had a replication capacity of 97+/-29%, but only 2.4+/-0.9% for K65R+K70E and 0.01% for K65R+K70E+M184V mutants. K65R+K70E phenotypic fold changes for abacavir, lamivudine and tenofovir were comparable to reported values for K65R alone. In molecular dynamic simulations, the epsilon-amino group of K65 was positioned 2.7+/-0.1A from the gamma-phosphate of the dTTP ligand and stabilized the triphosphate. In the R65 mutant, this distance increased to 4.2+/-0.4A and the interaction energy with the ligand was less favorable, but the K70 epsilon-amino group was repositioned closer to the gamma-phosphate and had a more favorable interaction energy. In the double mutant, E70 could not stabilize the gamma-phosphate, resulting in a more severe defect. The net effect of the atomic-level changes in the double mutant may be to destabilize the pyrophosphate leaving group of the ligand, more severely affecting the catalytic rate of the polymerization reaction than the R65 single mutation.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Computer Simulation; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutagenesis, Site-Directed; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir

To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial.. PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).. 128 ART-naïve children were randomised to zidovudine\\lamivudine (n = 36), zidovudine\\abacavir (45) or lamivudine\\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.. Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\\lamivudine, zidovudine\\abacavir and lamivudine\\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\\lamivudine, 50%/25% zidovudine\\abacavir and 79%/63% lamivudine\\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\\abacavir (K65R, L74V, Y115F, M184V).. Five year data demonstrate that lamivudine\\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\\lamivudine or zidovudine\\abacavir, and should be preferred as first-line NRTI backbone.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Dideoxynucleosides; Drug Resistance, Viral; Follow-Up Studies; Growth; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF).. An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%.. Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response.. Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant.

Topics: Adenine; Alleles; Didanosine; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Organophosphonates; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals.. HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI).. Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml.. No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.

Topics: Adult; Area Under Curve; Atazanavir Sulfate; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; HIV; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

Suspected hypersensitivity is the main reason for the early discontinuation of abacavir. After the observation that the risk of hypersensitivity correlated with ethnicity, the presence of the HLA allele B5701 was found to be the strongest retrospective predictor of hypersensitivity. Two prospective cohorts have since demonstrated a significant reduction in abacavir hypersensitivity rates with the use of prospective human leukocyte antigen screening. We describe our experience of prospective HLA-B5701 testing and the impact on rates of abacavir hypersensitivity.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; Histocompatibility Testing; HIV Infections; HIV Reverse Transcriptase; HLA-B Antigens; Humans; Male; Prospective Studies; Reverse Transcriptase Inhibitors

To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen.. A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load.. A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50copies/ml (P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients (P=0.996) had responded to <50copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points.. This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome; Zidovudine

A one-tablet, once-daily abacavir/lamivudine fixed-dose combination (FDC) has been recently approved to treat HIV-1 infection.. A randomized, open-label, parallel-group, multicenter study to compare the efficacy and safety of the FDC group to the separate entities (SE) group, in combination with tenofovir and a new protease inhibitor or nonnucleoside reverse transcription inhibitor in antiretroviral-experienced adults experiencing virologic failure (VF). Eligible subjects had viral loads >1000 copies/mL with < or =3 nucleoside reverse transcription inhibitor-associated mutations. The primary efficacy end point was time-average changed from baseline (average area under the curve minus baseline) in plasma HIV-1 RNA over 48 weeks.. A total of 186 subjects were enrolled. The average area under the curve minus baseline was -1.65 and -1.83 log10 copies/mL in the FDC and SE groups, respectively (intention to treat; 95% confidence interval: -0.13, 0.38). Patients in the FDC (50%) and SE groups (47%) achieved viral loads <50 copies/mL based on the time to loss of virologic response algorithm. VF was low and similar in both groups (FDC, 16%; SE, 18%). Tolerability was similar between the 2 groups.. The FDC group had noninferior efficacy over 48 weeks to the SE group in treatment-experienced subjects with VF.

Topics: Adult; Aged; Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Safety

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943.. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Topics: Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen.. To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection.. The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG.. Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen).. Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels > or =200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes.. Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 (72,444) copies/mL and CD4 cell count of 240 cells/mm3 were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different.. In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit.. clinicaltrials.gov Identifier: NCT00013520.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; RNA, Messenger; Viral Load; Zidovudine

Long-term antiretroviral therapy, while dramatically reducing HIV-related morbidity and mortality, is associated with metabolic and morphological changes. Peripheral fat loss, lipoatrophy, appears most associated with prolonged therapy with thymidine nucleoside analogues.. A randomized, open-label, comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate (DF) or abacavir in 105 individuals on successful antiretroviral therapy with clinically evident moderate to severe lipoatrophy.. Individuals were randomized to tenofovir DF (52) or abacavir (53). The switch was well tolerated and the majority of patients completed 48 weeks of study. One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events. Both groups similarly maintained virological control. Limb fat mass increased similarly in both groups: mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups, respectively [mean 95% confidence interval for difference, -154.3 (range -492.8 to 184.3)]. This change from baseline was statistically significant in both groups (tenofovir DF, P = 0.01; abacavir, P = 0.0001). Mean total cholesterol, low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir. The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir.. Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks. Tenofovir DF may have modest advantages over abacavir for changes in lipids. Peripheral lipoatrophy, when clinically apparent, resolves slowly following treatment switching.

Topics: Adenine; Adult; Aged; Anti-HIV Agents; Biomarkers; Body Fat Distribution; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lipids; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine

Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations.. Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out.. A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment.. No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Viral Load; Zidovudine

Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects.. An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors.. At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments.. In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Least-Squares Analysis; Lipids; Male; Middle Aged; Pilot Projects; Reverse Transcriptase Inhibitors; Triglycerides

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI+d4T) vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P<0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI+d4T or ABC+3TC.

Topics: Adult; Anti-HIV Agents; Body Composition; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Stavudine

The long intracellular half-life of abacavir (ABC) supports its once-daily use, and this would be expected to simplify treatment if ABC could be given as part of a complete once-daily regimen. A randomized double-blind clinical trial compared the efficacy and safety of 600 mg of ABC administered once daily (n = 384) versus 300 mg of ABC administered twice daily (n = 386) in combination with 300 mg of lamivudine (3TC) and 600 mg of efavirenz (EFV) administered once daily in antiretroviral-naive patients over 48 weeks. The baseline median plasma HIV-1 RNA level was 4.89 log10 copies/mL (44% with viral load >100,000 copies/mL), and the median CD4 cell count was 262 cells/mm. ABC administered once daily was non-inferior to the twice-daily regimen, with 66% and 68% of patients in these respective treatment arms achieving a confirmed plasma HIV-1 RNA level <50 copies/mL (95% confidence interval: -8.4%, 4.9%). The ABC once-daily and twice-daily regimens were similar with respect to infrequency of virologic failure (10% vs. 8%), emergence of resistance mutations, CD4 cell increases from baseline (median, 188 vs. 200 cells/mm), safety profile, and incidence of ABC-related hypersensitivity reactions (9% vs. 7%). ABC administered once daily in combination with 3TC and EFV administered once daily was non-inferior to the ABC twice-daily dosing schedule when combined with 3TC and EFV over 48 weeks.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Oxazines; RNA, Viral; Treatment Outcome; Viral Load

Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy.. A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA < or = 400 copies/mL after > or = 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24).. Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (< 400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; < 50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed.. ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Hydroxyurea; Male; Middle Aged; Oxazines; RNA, Viral; Time Factors; Treatment Failure

There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children.. Children aged 2-13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0-24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response.. 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1-12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0-24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2-6 versus 6-13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2-6 versus 6-13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24.. AUC0-24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.

Topics: Administration, Oral; Adolescent; Age Factors; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cross-Over Studies; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Netherlands; United Kingdom

The aim of the study was to evaluate the safety and efficacy of abacavir (ABC) and efavirenz (EFV) instead of a protease inhibitor (PI) in HIV-1-infected subjects treated with two nucleoside reverse transcriptase inhibitors (NRTIs) and one PI with undetectable viral loads (< 50 HIV -1 RNA copies/mL). To be eligible for inclusion, patients had to have a history of viral load < 400 copies/mL for at least 3 months and had to be naive to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed.. An open-label, single-centre pilot study of duration 48 weeks was conducted. ABC was added to the original treatment with two NRTIs and one PI at baseline, and at week 6 the PI was replaced by EFV. At each study visit, CD4 cell count, viral load [measured by polymerase chain reaction (PCR)] and clinical chemistry were measured. Fasting blood samples were taken at baseline and at weeks 12, 24, 36 and 48 to measure levels of cholesterol [high-density lipoprotein (HDL)/low-density lipoprotein (LDL)], triglycerides, insulin and C-peptide. Additionally, an oral glucose tolerance test (OGTT) was performed. A bioelectric impedance analysis (BIA) and a single slice abdominal and mid-thigh computed tomography (CT) scan were carried out to assess changes in body composition.. Thirty patients were included in the study. Three patients experienced ABC-hypersensitivity and one patient demonstrated virological failure caused by nonadherence. At week 48, all remaining patients had viral loads < 50 copies/mL with stable CD4 counts. The fasting metabolic parameters and abdominal fat distribution remained unchanged.. In heavily pretreated patients, ABC and EFV in combination provide an effective, simplified and well-tolerated alternative to PI treatment.

Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Body Composition; Cholesterol, HDL; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Pilot Projects; Reverse Transcriptase Inhibitors; Statistics, Nonparametric; Viral Load

To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir.. NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements.. Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed.. Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

Topics: Adult; Alkynes; Anthropometry; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Glucose; Cholesterol; Cholesterol, HDL; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Triglycerides

The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Male; Models, Biological; Reverse Transcriptase Inhibitors; Software

The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen.. Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase.. The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057).. After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Patient Compliance; RNA, Viral; Zidovudine

To assess the virologic noninferiority of an antiretroviral treatment simplification with coformulated zidovudine/lamivudine/abacavir (group 1) vs. coformulated zidovudine/lamivudine plus nevirapine (group 2) in HIV-1-infected patients receiving successful first-line highly active antiretroviral therapy.. This is a prospective, multicenter, open-label, comparative, randomized, noninferiority study. A delta of 15% for differences in virologic suppression <200 copies/mL between groups was prespecified with a 1-sided 0.025 significance level.. A total of 134 patients were included into this study: 68 were allocated to group 1 and 66 to group 2. By intention-to-treat analysis (switch equals failure), the percentage of virologic suppression <200 copies/mL (<50 copies/mL) at week 48 was 71.0% (65.1%) and 73.0% (63.3%) in groups 1 and 2, respectively (estimate for differences [<200 copies/mL]: -2.1, 95% CI: -17.4-13.1, P=0.783). Thirteen and 14 patients in groups 1 and 2, respectively, discontinued therapy due to adverse events. Dyslipidemia improved in both groups, with a higher improvement in low-density lipoprotein cholesterol (P=0.049) in group 1.. Group 1 is not inferior to group 2 regarding virologic suppression <200 copies/mL. Both strategies improve lipid profile.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Nevirapine; Patient Compliance; Patient Satisfaction; Prospective Studies; Quality of Life; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.

Topics: Adenine; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Organophosphonates; Pilot Projects; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; RNA, Viral; Sequence Analysis, Protein; Tenofovir; Treatment Failure; Viral Load

The NEFA Study was a randomized study comparing nevirapine (NVP), efavirenz (EFV) or abacavir (ABC) as substitutes for protease inhibitors in a large group of HIV-1-infected patients successfully treated with antiretroviral regimens containing protease inhibitors.. To evaluate genotype and phenotype resistance patterns among patients who have experienced virological failure under one of the three study arms.. Patients with virological failure, defined as two consecutive determinations of HIV-1 RNA > 200 copies/ml, were analysed for phenotypic susceptibility and HIV-1 mutations.. Of the 460 patients included in the study, 51 (11%) experienced virological failure after 24 months of follow-up while on assigned study medication. A higher proportion of patients in the ABC [25 (17%)] than in the NVP [14 (9%)] or EFV [12 (8%)] arms selected resistance to the study drug (P = 0.04). Moreover, a much higher number of resistance mutations to one or more of the backbone nucleoside reverse transcriptase inhibitor drugs contained in the failing regimen were observed in the ABC than in the EFV or NVP arms. In general, there was a good concordance among genotype and phenotype resistance testing, except for ABC, stavudine and didanosine, where phenotypic resistance testing added valuable information (fold change in the median inhibitory concentration).. Cross-resistance involving nucleoside reverse transcriptase inhibitor drugs might explain the higher risk of virological failure in patients switched to ABC-containing antiretroviral therapy. Phenotypic resistance testing may be helpful in interpreting unclear genotypic results.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Follow-Up Studies; Genotype; HIV Infections; HIV-1; Humans; Middle Aged; Mutation; Nevirapine; Oxazines; Phenotype; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure

Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily.. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log(10) copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of > or =1.0 log(10) copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions.. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log(10) copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from > or =8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P<.001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL.. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

Topics: Adenine; Adolescent; Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Time Factors; Treatment Failure

Abacavir (ABC) and lamivudine (3TC) administered twice daily were compared with an ABC + 3TC fixed-dose combination (Epzicom, Kivexa; EPZ) administered once daily, both in combination with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).. Two hundred sixty HIV-infected subjects with more than 6 months of ABC and 3TC administered twice daily plus a PI or NNRTI with an HIV-1 RNA level less than 400 copies/mL for more than 3 months and a CD4 count greater than 50 cells/mm were randomized 1:1 to ABC + 3TC administered twice daily or EPZ administered once daily.. At baseline, median time on ABC and 3TC administered twice daily was 22 months, and median CD4 count and HIV-1 RNA level were 554 cells/mm and <50 copies/mL, respectively. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily based on the proportion of nonvirologic failures (confirmed HIV-1 RNA level > or =1265 copies/mL; 90% confidence interval: -3.4 to 6.4; (intent to treat [ITT]: missing [M] = failure [F]). Proportions with an HIV-1 RNA level <50 copies/mL were 81% of those taking EPZ once daily and 82% of those taking ABC + 3TC twice daily at week 48 (ITT: M = F). Virologic failure was rare (2 patients taking the once-daily regimen, 4 patients taking the twice-daily regimen). There was a low incidence of grade 2 through 4 adverse events (AEs) and no drug-related serious AEs or hypersensitivity reactions.. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily in a regimen containing an NNRTI or a PI over 48 weeks. A dual-nucleoside backbone of ABC and 3TC administered once or twice daily is effective, durable, and well tolerated.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Treatment Refusal; Viral Load

This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (tau), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUC(tau,ss) versus the AUC from 0 h to infinity was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA ( approximately 2 log(10) copies/ml) and increased CD4(+) cell counts ( approximately 100 cells/mm(3)) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Area Under Curve; Carbamates; CD4 Lymphocyte Count; Cross-Over Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphates; RNA, Viral; Sulfonamides

Stavudine use is a contributing factor for lipoatrophy, whereas use of abacavir or zidovudine is less likely to cause this complication. The TARHEEL study was a 48-week, open-label study that assessed changes in lipoatrophy after abacavir (86 patients [73%]) or zidovudine (32 patients [27%]), 300 mg twice daily, was substituted for stavudine for 118 human immunodeficiency virus (HIV)-infected patients (HIV type 1 RNA level, <400 copies/mL) with virological suppression who had developed lipoatrophy after > or =6 months of stavudine-based treatment. At week 48, full-body dual-energy x-ray absorptiometry demonstrated a median increase in arm fat of 35%, leg fat of 12%, and trunk fat of 18%, compared with the baseline level. These improvements coincided with fat gain in lipoatrophic areas that was documented by computerized tomography. Results of a "body image" questionnaire showed that a substantial percentage of patients reported some or a lot of fat gain in the arms (22%), legs (18%), buttocks (19%), and face (27%). HIV suppression was maintained over the study period. In conclusion, replacing stavudine with abacavir or zidovudine resulted in improvement in stavudine-induced lipoatrophy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV; HIV Infections; HIV-1; Humans; Lipodystrophy; Male; Middle Aged; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

To compare the efficacy, durability, and tolerability of GW433908 (908), 1400 mg twice-daily (BID), with nelfinavir (NFV), 1250 mg BID.. This was an international, multicenter, randomized, open-label study (NEAT) in antiretroviral therapy (ART)-naive HIV-infected adults with plasma HIV-1 RNA (vRNA) at screening > or =5000 copies/mL (c/mL). Patients were randomly assigned to 908 or NFV (2:1) for a minimum of 48 weeks, with a background of abacavir (ABC) and lamivudine (3TC).. A total of 166 patients received randomized treatment with 908 BID and 83 received NFV BID. The population was diverse with regard to race and gender (76% Hispanics and blacks, 31% female) and had advanced HIV disease at screening (45% had vRNA >100,000 c/mL, 48% had CD4 cell counts <200 cells/mm3, 20% had a history of Centers for Disease Control class C events). After 48 weeks of study by an intention-to-treat rebound or discontinuation = failure analysis, a greater proportion of patients in the 908 BID group (66%) than the NFV BID group (51%) achieved vRNA <400 c/mL. Furthermore, more patients with screening vRNA >100,000 c/mL (67 vs. 35%) or CD4 <50 cells/mm3 (48 vs. 24%) achieved undetectable viral loads taking 908 BID compared with NFV BID, respectively. Favorable immunologic responses were observed for both groups. Diarrhea, which was more common in the NFV BID group (18 vs. 5%), was the only drug-related grade 2-4 adverse event with a significant difference (P = 0.002) in incidence between groups.. Administration of 908 BID resulted in a potent and sustained antiretroviral response, notably in ART-naive patients with advanced HIV disease. GW433908 was generally well tolerated and provides a convenient dosing option without food or fluid restrictions.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Organophosphates; Reverse Transcriptase Inhibitors; RNA, Viral; Sulfonamides

This study evaluated whether intensification of standard antiretroviral therapy with abacavir, with or without efavirenz, leads to better viral suppression and acceleration of the rate of HIV-1 decay. Ten HIV-1-infected individuals were enrolled in a prospective, open-label study and received standard, combination antiretroviral therapy with either 3 or 4 agents. The rate of decay of the HIV-1 latent reservoir and the frequency of intermittent viremia were compared between 5 patients who underwent treatment intensification and 5 control subjects with comparable baseline characteristics. When compared with control patients, the median half-life (t1/2) of the latent reservoir decreased from 31 to 10 months (P = 0.016) in subjects who had treatment intensification. The frequency of intermittent viremia/year also decreased in 4 of 5 individuals following intensification (2.4/y vs. 0.8/y). These data suggest that ongoing virus replication during standard antiretroviral therapy is due, in part, to the inadequate antiviral potency of current regimens. Despite better viral suppression, treatment intensification did not completely block viral replication, as evidenced by continuing intermittent viremia in some individuals. Additional studies are needed to understand the host- and pathogen-related determinants of incomplete pharmacologic control of HIV-1 replication.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Pilot Projects; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Virus Latency; Virus Replication

Antiviral efficacy and serum lipids were investigated following a switch from long-term successful protease inhibitor based antiretroviral treatment (PI-ART) to abacavir-based ART in 29 patients who have been followed for 28 months thereafter. Virologic failure occurred within 3 months in 21% (6/29) of the patients, and abacavir hypersensitivity in 1 individual. The remaining 22 patients continue to have HIV RNA < 50 copies/ml after 28 months with a CD4 increase from 605 +/- 265 x 10(6)/l to 798 +/- 366 x 10(6)/l (p < 0.001). All virologic failing patients had been on long-term unsuccessful nucleoside reverse transcriptase inhibitor (NRTI) therapy before PI-ART as compared to 32% (7/22) of the virologic non-failing patients (p < 0.01). The viral strains from the virologic failing patients harboured 3-6 reverse transcriptase (RT) mutations, including the V118I mutation in 5/6 cases prior to PI-ART or at viral rebound. Only the V118I RT mutation was statistically more common among virologic failing than non-failing NRTI pretreated patients (p < 0.05). Stepwise multiple regression analysis for viral failure resulted in a model with only the V118I RT mutation entering the model (p < 0.01). The LDL cholesterol and triglyceride values decreased and the HDL cholesterol increased after the switch to abacavir-based ART (p < 0.01, p < 0.05, p < 0.05, respectively). In conclusion, viral failure was associated with prior mono- or dual-NRTI treatment and the occurrence of the V1181 RT mutation, persisting despite long term viral control. The selection process for patients suitable for treatment simplification to abacavir-based ART should contain a detailed antiretroviral treatment history.

Topics: Adult; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Pharmacogenetics; Probability; Prospective Studies; Regression Analysis; Reverse Transcriptase Inhibitors; Risk Assessment; RNA-Directed DNA Polymerase; Single-Blind Method; Statistics, Nonparametric; Treatment Failure; Viral Load; Virus Replication

To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC).. Long-term follow-up (104 weeks) of a randomized, open-label study.. Seventeen ambulatory HIV clinics in Australia and London.. Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43).. At week 24, all control patients could switch to ABC. Of the original 111 patients randomized, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks.. The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA).. At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008). On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm. Visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve.. In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.

Topics: Absorptiometry, Photon; Adipose Tissue; Anti-HIV Agents; Body Composition; Bone Density; Dideoxynucleosides; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited.. This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz.. We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups.. In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.

Topics: Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Zidovudine

We compared the long-term immunologic and virologic efficacy of the dual- and triple-nucleoside therapy for HIV infection. This was a retrospective analysis of 2 randomized clinical trials in antiretroviral-naive patients. In the dual-nucleoside group, 15 started with didanosine (ddI) monotherapy and then added stavudine (d4T) after 24 weeks, 63 started with various doses of d4T and ddI, and 53 started with zidovudine (ZDV) and lamivudine (3TC). In the triple-nucleoside group, 53 started with ZDV, 3TC, and ddI. After 48 weeks, patients who were not failing were randomized to immediate (before treatment failure) versus delayed (at the time of virologic failure) switching from ddI and d4T to ZDV and 3TC or vice versa and from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC). Failure was defined as a plasma HIV-1 RNA level>or=1 log10 above nadir or >or=10,000 copies/mL when nadir was <500 copies/mL. Patients failing therapy before week 48 received the new treatment as in the immediate switching group. Hydroxyurea was added to the last treatment regimen if patients failed after week 96. CD4 count and plasma HIV-1 RNA level (branched DNA assay with a cutoff point of 50 copies/mL) at week 144 were analyzed by intention to treat. Compared with the dual-nucleoside group, the triple-nucleoside group had a higher proportion of patients with <50 copies/mL at 144 weeks (60% vs. 18%; P<0.001), higher median CD4 count (388 cells/microL vs. 346 cells/microL; P=0.018), and longer duration of response, defined as the time from onset of viral suppression (<500 copies/mL) to the time of treatment failure (the first of 2 consecutive HIV-1 RNA measurements >500 copies/mL never followed by 2 consecutive visits showing suppressible viremia to <500 copies/mL) or discontinuation from the study (144 weeks vs. 104 weeks; P=0.002). Multivariate regression analyses showed that significant predictors for treatment success, defined as a plasma viral load <50 copies/mL at week 144, were asymptomatic clinical status at enrollment, a baseline plasma viral load

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Retrospective Studies; RNA, Viral; Stavudine; Thailand; Time Factors; Zidovudine

Stavudine (d4T) has been observed in clinical trials and cohort studies to be more often implicated in cases of hyperlactatemia than other nucleoside reverse transcriptase inhibitors, possibly because of its relatively greater propensity to induce mitochondrial toxicity. The ESS40010 study was a 48-week, open-label, switch study that assessed changes in serum lactate levels and signs/symptoms of hyperlactatemia after substitution of abacavir (n = 86) or zidovudine (n = 32) for d4T in 118 virologically suppressed HIV-infected patients (HIV-1 RNA <400 copies/mL) who had developed serum lactate concentrations > or =2.2 mmol/L (n = 16) or had remained normolactatemic (n = 102) after receiving > or =6 months of d4T-based treatment. Median serum lactate decreased significantly below baseline at week 24 (-0.15 mmol/L, P = 0.0002) and week 48 (-0.15 mmol/L, P = 0.0015). In 10 hyperlactatemic patients in whom d4T was discontinued, serum HIV-1 RNA levels rebounded over the ensuing 31 days, but virologic suppression (HIV-1 RNA <400 copies/mL) was regained when treatment using abacavir or zidovudine was subsequently instituted. In the group with elevated lactate at baseline, symptoms of hyperlactatemia improved in 8% to 23% of patients, did not change in 69%, and worsened in 8%. Serum transaminases, which had been elevated while patients received d4T, normalized after d4T discontinuation and remained in the normal range after the switch to abacavir or zidovudine. Overall, in patients with d4T-associated hyperlactatemia, stopping d4T results in normalization of lactate and a rebound in viral load; restarting treatment using abacavir or zidovudine subsequently maintains normal lactate levels and rapidly leads to a return of virologic suppression.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Lactates; Male; Middle Aged; Recurrence; Stavudine; Treatment Outcome; Viral Load; Zidovudine

An equivalence (non-inferiority) trial comparing antiviral response, tolerability, and adherence with a triple nucleoside regimen containing abacavir 300 mg (ABC) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet (COM) twice daily vs. a regimen containing the protease inhibitor indinavir (IDV) 800 mg three times daily plus COM twice daily (IDV/COM) in antiretroviral-naïve, HIV-infected patients.. Adult patients with plasma HIV-1 RNA levels > or = 5000 copies/mL and CD4+ cell counts > or = 100 cells/mm(3) were randomized to receive open-label ABC/COM (n = 169) or IDV/COM (n = 173) for 48 weeks. The intent-to-treat (ITT) population was the primary population evaluated. ITT: switch/missing equals failure (ITT: S/M = F) and as-treated (AT) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50 copies/mL at each clinic visit. In the ITT: S/M = F analysis, patients who switched treatment or had missing values were considered treatment failures; the AT analysis examined virologic data only while patients received study treatment. ABC/COM was considered equivalent (non-inferior) to IDV/COM if the lower limit of the 95% confidence intervals (CIs) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400 copies/mL exceeded -15% at week 48.. The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). ABC/COM met the criterion of equivalence to IDV/COM. In the ITT: S/M = F analysis at Week 48, a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400 copies/mL (66% [109/164] vs. 50% [82/165]; treatment difference 16.6%, 95% CI (6.0, 27.2), p = 0.002) and HIV-1 RNA < 50 copies/mL (60% [99/164] vs. 50% [83/165]; treatment difference 9.6%, 95% CI [-1.1, 20.2]), whereas the AT analysis showed similar proportions achieving these endpoints (< 400 copies/mL: 85 vs. 83%; < 50 copies/mL: 79 vs 81%). Comparable proportions of patients with screening HIV-1 RNA values > 100 000 copies/mL achieved HIV-1 RNA < 400 copies/mL (ABC/COM: 60% [35/58]; IDV/COM: 51% [33/65]; treatment difference 9.6%, 95% CI [-7.9, 27.1]; ITT: S/M = F analysis). A significantly greater proportion taking ABC/COM were > or = 95% adherent (72% [109/151] vs. 45% [70/154] with IDV/COM, p < 0.001). Median increases from baseline in CD4+ cell counts were similar in the two treatment groups (+148 vs. +152 cells/mm(3)). Significantly more patients on IDV/COM reported drug-related adverse events (87% [142/165] vs. 65% [108/164] with ABC/COM, p < 0.001), similar proportions discontinued treatment due to adverse events (13 vs. 10%), and a slightly greater proportion in the ABC/COM group reported serious adverse events (13 vs. 8%). About half of the latter comprised suspected ABC-related hypersensitivity reactions (overall rate, 6%). Most adverse events were gastrointestinal in nature in both treatment groups.. ABC/COM was at least equivalent to IDV/COM over 48 weeks in the treatment of antiretroviral-naïve patients. ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM. The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata, adherence was not monitored electronically, and bias could not be ruled out due to the open-label study design.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; RNA; Surveys and Questionnaires; Therapeutic Equivalency; Treatment Outcome; Zidovudine

To compare dosing convenience and adherence with abacavir (ABC) 300 mg plus a fixed-dose lamivudine 150 mg/zidovudine 300 mg combination tablet (COM) twice daily versus indinavir (IDV) plus COM twice daily in treatment-naïve, HIV-1-infected adults; and to evaluate the association among difficulty taking antiretroviral regimens, adherence, and virologic efficacy.. An open-label, randomized, multicenter, international study compared the COM/ABC and IDV/COM regimens with respect to self-reported adherence and regimen convenience over 48 weeks. Logistic regression analysis (LRA) was done on a patient sub-sample from both groups to evaluate predictors of adherence and virologic response at last time-point on randomized therapy (LTORT).. The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). Of 329 patients who were randomized and received treatment, 315 (96%) provided adherence data. Significantly more patients in the ABC/COM group than in the IDV/COM group reported > or = 95% adherence to therapy (76 vs 58%, p < 0.001) and no difficulty in taking their regimen (91 vs 61%, p < 0.001). In both groups, the highest probability of HIV-1 RNA < 400 copies/mL occurred when median adherence was > or = 95%. The probability of HIV-1 RNA < 400 copies/mL declined more rapidly in the IDV/COM group as adherence rates decreased. LRA showed that no difficulty taking any of the drugs in the regimen, ABC/COM treatment group, and male gender were independent significant predictors of > or = 95% adherence (p < 0.05). Median adherence and baseline HIV-1 RNA were significant predictors of HIV-1 RNA < 400 copies/mL (p < 0.05).. Patients reported greater ease of use and superior adherence to ABC/COM than IDV/COM. Patient-reported difficulty taking drugs in a regimen was predictive of reduced adherence, and both of the latter factors were predictive of poorer virologic outcome. Adherence levels of > or = 95% in both treatment groups maximized the probability of patients achieving an HIV-1 RNA < 400 copies/mL.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Patient Compliance; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Outcome; Zidovudine

Zidovudine, lamivudine, and efavirenz comprise a highly effective and well-tolerated triple regimen for antiretroviral-naive patients. Evaluating other unique nucleoside reverse-transcriptase inhibitor (NRTI) combinations for long-term viral suppression is desirable.. This multicenter, randomized, double-blind noninferiority clinical trial compared the efficacy and safety of abacavir with that of zidovudine plus lamivudine and efavirenz in 649 antiretroviral-naive HIV-infected patients. The primary objective was a comparison of proportions of patients achieving plasma HIV-1 RNA levels

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oxazines; RNA, Viral; Zidovudine

To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen.. Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs + other ART. The median follow-up was 48 weeks (range week 16-72).. Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had > or = 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V1081 (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the G190 mutations (OR=8.9, P<0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and 154V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates.. Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Oxazines; Salvage Therapy; Sulfonamides

We evaluated in an open-label, randomized, controlled, pilot trial if the re-emergence of previously selected resistant strains, harbouring M184V mutation, could be modulated by the use of different drug associations as components of the new antiretroviral regimens. In addition, we assessed the clinical relevance of this mutation on the management of heavily pretreated HIV-infected patients. The primary end-point of the study was the reselection of M184V mutation. Secondary end-points were the variation over time of HIV RNA plasma levels and CD4 cell counts and the progression of HIV disease. The primary population for efficacy analysis was the intention-to-treat exposed population. After a run-in phase consisting in a new treatment regimen excluding either lamivudine (3TC) or abacavir (ABC) so as to clear the previously documented M184V mutation, 18 patients with an HIV RNA plasma level greater than 10000 copies/ml were randomized to receive an antiretroviral drug regimen (at least three drugs) including either ABC or the association of ABC+3TC. All patients were naive to ABC. The M184V mutation reappeared in 1/9 patients in the ABC group and in 8/9 patients in the ABC+3TC group (P<0.003, 95% CI: 0.5-1). In the ABC group we observed a rapid decrement of viral load that was maintained throughout all the study period (P<0.05). On the contrary, in the ABC+3TC group, after a transient decrement at 2 months, a progressive increment towards baseline values was observed. The proportion of patients with a viral load reduction of at least 0.5 logs at 12 months was significantly higher in the ABC group: 8/9 patients vs 3/9 (P=0.05, 95% CI: 0.2-0.92). Similarly, from an immunological point-of-view, the increase at all time points (since randomization) in CD4 cell count was statistically significant in the ABC group (P<0.01), while no difference was observed in the ABC+3TC group. The possibility of a successful use of ABC in salvage regimens opens alternative therapeutic options for heavily pretreated patients with previously documented M184V mutation. Further studies should clarify whether this is true for other drugs of the nucleoside analogues class.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Mutation; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy; Viral Load

To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patients.. Open-label study in HIV-1-infected ART-naive adults, randomized to receive either Combivir (lamivudine 150 mg/zidovudine 300 mg twice daily) + abacavir (300 mg twice daily), or Combivir + nelfinavir (750 mg every 8 h) for 48 weeks. Plasma HIV-1 RNA, CD4 cell count and adverse events were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48.. 195 subjects (131 men, 64 women), median age 34 years, were randomized: 98 received combivir/abacavir and 97 combivir/nelfinavir. Baseline median plasma HIV-1 RNA was 4.2 log10 copies/ml [Interquartile range (IQR): 3.7-4.5.2] and 4.1 log10 copies/ml (IQR: 3.8-4.6), respectively. Baseline median CD4 cell count was 387 cells/mm3 (IQR: 194-501) and 449 cells/mm3 (IQR: 334-605), respectively. Nine patients (3 vs 6, respectively) did not start treatment or did not have any available efficacy data. At week 48, using the intent to treat analysis (switch/missing equals failure), plasma HIV-1 RNA was <50 copies/ml in 54/95 (57%) and 53/91 (58%) of subjects, respectively. Median CD4 increase was +110 and +120 cells/mm3, respectively. Possible hypersensitivity reactions to abacavir were reported in four subjects (4%).. The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults, with comparable antiviral activity to a nelfinavir-containing regimen at week 48.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Treatment Outcome; Zidovudine

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Denmark; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Genome, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutation; Phenotype; Reverse Transcriptase Inhibitors; Salvage Therapy; Stavudine; Time Factors; Treatment Failure

Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C(min)) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C(min) for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum C(min) range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C(min) for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (V(ss)/F) (P = 0.25), and half-life (t(1/2)) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C(max)s) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the C(min)s were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), V(ss)/F (P = 0.33), and t(1/2) (P = 0.37) were similar regardless of the dosing regimen. The median C(max), C(min), CL/F, V(ss)/F, and t(1/2) for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Male; Oxazines; RNA, Viral

The mechanisms by which dyslipidemia and lipoatrophy develop during antiretroviral therapy are not clear. No treatment of lipoatrophy is currently established.. This was an open-label randomized study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of <50 copies/mL. Patients switched d4T to abacavir (ABC) (group 1), a PI or NNRTI to ABC (group 2), or d4T and PI or NNRTI to ABC plus AZT (group 3). Patients were followed-up with fasting blood levels, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT) scans for 48 weeks.. Thirty patients were included, with 27 completing 48 weeks of therapy. One ABC hypersensitivity reaction was the only serious adverse event. All patients' viral loads remained at <50 copies/mL. CD4 cell counts rose in groups 2 and 3 but fell modestly in group 1. Total and low-density lipoprotein cholesterol improved significantly in groups 2 and 3. Triglycerides fell significantly in group 2. In contrast, total, arm, and leg fat mass (by DXA) rose significantly in group 1 but fell modestly in groups 2 and 3. Visceral adiposity (by CT scan) was unaffected in all groups.. Abacavir represents a virologically effective replacement for d4T, PI, or NNRTI in persons on successful first-line therapy. Replacement of a PI or NNRTI with ABC leads to modest improvement in both cholesterol and triglycerides. Replacement of d4T with ABC leads to modest improvements in fat mass.

Topics: Adult; Body Composition; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Insulin Resistance; Male; Reverse Transcriptase Inhibitors; Stavudine; Time Factors

HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients.. The investigation was a prospective, randomized, controlled, open-label study.. The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor.. Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir.. Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed.. There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy.. A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor.

Topics: Adult; Body Composition; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Male; Middle Aged; Stavudine; Zidovudine

From a study of 71 HIV-1-infected patients receiving abacavir in combination with 1 of 5 different HIV-1 protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir, or amprenavir), we found that the baseline HIV-1 RNA levels were highly predictive of the viral decay rates. The baseline HIV-1 RNA levels were negatively correlated with the first phase viral decay rates (r = -0.77, P < 0.001) and positively correlated with the second phase viral decay rates (r = 0.68, P < 0.001). In addition, the first phase viral decay rate was positively correlated with CD4+ cell increases. No significant correlation was found between viral decay rates and longer term (24 weeks) virologic responses, and no difference in viral decay rates was found among the 5 study regimens. These data suggest that the potency of the 5 treatment regimens was similar and was not predictive of long-term virologic failure.

Topics: Adolescent; Adult; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load

We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved.. We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter.. At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients. Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups.. When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.

Topics: Adult; Aged; Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure

Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear.. Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks.. At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%.. The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Nelfinavir; Nervous System Diseases; Nevirapine; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Outcome

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Enfuvirtide; Female; Furans; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Peptide Fragments; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype.. DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARgamma, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype.. Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-stavudine, non-PI-containing HAART, P=0.006).. Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.

Topics: Adipocytes; Adipose Tissue; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cell Differentiation; Dideoxynucleosides; DNA, Mitochondrial; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Proteins; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; RNA, Messenger; Stavudine; Zidovudine

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors; Risk; RNA, Viral

A 24-week open-label clinical trial was conducted in 195 HIV-infected adults commonly underrepresented in research (35% female, 71% African American, 21% Hispanic, and 20% injection drug users [IDUs]) to evaluate the effect of an HIV educational program on efficacy and adherence with a simple, compact, twice-daily triple nucleoside regimen containing a lamivudine (150 mg)/zidovudine (300 mg) combination (COM) tablet plus abacavir (ABC), 300 mg. At baseline, the patients' median plasma HIV-1 RNA level was 4.18 log10 copies/mL and the median CD4+ cell count was 379 cells/mm3. Patients were randomized 1:1 to 4 modules of the Tools for Health and Empowerment HIV education intervention plus routine counseling (EI + RC; n = 96) or to routine counseling alone (RC; n = 99). No differences between the EI + RC and RC treatment arms were observed with respect to the proportion of patients achieving plasma HIV-1 RNA levels <40 copies/mL (60% [33/55] vs. 55% [38/69]; P = 0.529) or <400 copies/mL (80% [44/55] vs. 80% [55/69]; P = 0.689) at week 24 (intent-to-treat observed analysis), increase in median CD4 cell count above baseline at week 24 (78.3 vs. 104.8 cells/mm3; P = 0.498), or mean overall adherence rates as measured by the Medication Event Monitoring System (MEMS) (70% vs. 74%). COM + ABC was generally well tolerated, and no association was observed between interruptions in treatment and the development of ABC hypersensitivity (5 suspected cases). In conclusion, in underrepresented patients, the EI used in this study did not affect the efficacy and adherence results with ABC + COM to any greater degree than did RC.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Patient Compliance; Patient Education as Topic; RNA, Viral; Zidovudine

To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients.. Randomized, open-label, parallel-group, multicenter, formulation-switch study.. Twenty seven outpatient treatment sites.. Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4+ cell counts above 200 cells/mm3 who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC.. Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks.. The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4+ cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred.. Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden.

Topics: Adolescent; Adult; Analysis of Variance; Anti-HIV Agents; Chemistry, Pharmaceutical; Confidence Intervals; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Zidovudine

Patients who have not received previous antiretroviral treatment (ART) have a high failure rate on the combination treatment of abacavir, lamivudine, and tenovir. We assessed the virological failure rate in eight patients with HIV-1 who switched to this combination after having complete virological suppression from their previous long-term ART (median 8.0 months, range 7.5-18.0). Five of the eight patients showed virological failure. Four of these five patients had either the K65R mutation, the M184V/I mutation, or both. This combination of drugs cannot therefore be recommended as alternative treatment in patients with HIV-1 who are fully virologically suppressed.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Organophosphonates; Organophosphorus Compounds; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome; Viral Load

TMC125, a next generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), demonstrated a remarkable decline of plasma HIV-1 RNA during a phase IIa study. We compared the initial rate of decline of plasma HIV-1 RNA achieved by TMC125 monotherapy with that of a triple class, five-drug regimen, containing drugs from all three currently licensed classes (zidovudine, lamivudine, abacavir, indinavir and nevirapine).. The decline in plasma HIV-1 RNA of 12 HIV-1 infected, antiretroviral (ART) naive patients treated for 1 week with TMC125 monotherapy was compared with that observed in the ERA study (n = 11). The plasma HIV-1 RNA elimination rate constant was calculated based on at least four plasma HIV-1 RNA measurements during the first week of treatment (first-order elimination) and compared using the Student's t test.. Median ages were 23 and 38 years for TMC125 and ERA patients, respectively (P = 0.001), median baseline plasma HIV-1 RNA levels were 4.2 and 4.8 log10 copies/ml (P = 0.001) and median baseline CD4 T-cell counts were 458 x 10(6) and 360 x 10(6) cells/l (P = 0.08). The median plasma HIV-1 RNA elimination rate constant was 0.68/day in TMC125 treated patients, and 0.56/day in ERA participants (P = 0.24). The median decline in plasma HIV-1 RNA after 7 days was 1.92 and 1.76 log10 copies (P = 0.77) and the median increase of CD4 T cells was 119 x 10(6) and 60 x 10(6) cells/l, respectively (P = 0.29).. Monotherapy with TMC125 in ART-naive, HIV-1-infected individuals resulted in a similar rate of decline of plasma HIV-1 RNA during 1 week of therapy as therapy with a five-drug regimen.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine

To evaluate the safety and efficacy of a protease inhibitor sparing, quadruple therapy (Combivir + abacavir + efavirenz) in antiretroviral treatment-naive HIV-1-infected adults.. Multicenter open-label pilot study. Clinical and biological assessments were performed at baseline and at weeks 2, 4, 8, 16, 24, 32, 40, 48.. Thirty-one subjects enrolled with a median baseline viral load (VL) of 4.69 log10 copies/mL and CD4 cell count of 322 cells/mm3. At week 48, 90% (intention-to-treat [ITT] switch included) and 77% (ITT switch = failure) patients had a VL <50 copies/mL. These results were similar in the population (n = 13) with a VL >100,000 copies/mL at baseline. Combivir + abacavir + efavirenz demonstrated an early antiretroviral response: 58% of patients had plasma HIV-1 RNA <50 copies/mL at week 8. Using a modified assay, the percentage of patients with VL <5 copies/mL at week 48 was 55% (17/31) and 42% (13/31) using ITT (switch included) and ITT (switch = failure), respectively. Median VL decreased by -4.0 log10 copies/mL at week 48 (ITT). Median CD4+ cell count change from baseline at week 48 was +129 cells/mm3 (ITT). Most patients experienced at least one drug-related adverse event that was not considered treatment-limiting by the investigator. There were no cases of abacavir hypersensitivity reactions.. Safety and efficacy results from this study demonstrated that the quadruple regimen Combivir/abacavir/efavirenz is generally safe and displays potent and durable antiretroviral activity in antiretroviral treatment-naive HIV-1-infected patients, offering a promising therapeutic option in a PI-sparing strategy.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; France; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

Nucleoside analogues are activated to their triphosphates, which compete with endogenous deoxynucleoside triphosphate (dNTP) pools to inhibit HIV reverse transcriptase. Hydroxyurea has been administered with nucleoside analogues to modulate intracellular dNTP pools and thus the ratio of drug triphosphate:endogenous triphosphate.. To examine changes in drug activation over time and investigate the effects of hydroxyurea on intracellular phosphorylation of antiretroviral nucleoside analogues.. A total of 229 HIV-infected individuals receiving abacavir, lamivudine and zidovudine were randomly assigned to receive or not nevirapine and hydroxyurea. Twenty-four patients were recruited to an observational substudy measuring intracellular drug triphosphate and dNTP concentrations at 0, 2, 6, 12, 24 and 48 weeks.. Drugs were extracted from isolated peripheral blood mononuclear cells before analysis of endogenous dNTP and drug triphosphates by primer extension assays.. Twenty-two out of 24 patients were followed to completion of the substudy. Hydroxyurea had no demonstrable effect on endogenous dNTP or drug triphosphate levels at any timepoint. However, the ratio of zidovudine triphosphate to endogenous deoxythymidine triphosphate was significantly increased with hydroxyurea. A significant decrease in lamivudine triphosphate (3TCTP) and the 3TCTP:endogenous deoxycytidine triphosphate ratio was seen over 48 weeks. In five patients who failed therapy in the first 24 weeks, significantly reduced 3TCTP was seen.. Hydroxyurea does not affect measurable pools of endogenous nucleosides in vivo. Decreased lamivudine phosphorylation over time may provide a novel pharmacological explanation for the mechanism of resistance to this drug.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Interactions; Drug Resistance, Viral; Female; HIV Infections; Humans; Hydroxyurea; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Nevirapine; Nucleosides; Phosphorylation; Reverse Transcriptase Inhibitors; Zidovudine

Prison inmates with human immunodeficiency virus (HIV) infection can be difficult to treat because of the complexity and intrusiveness of many combination antiretroviral therapy regimens. NZTA4007, a 24-week open-label, single-arm clinical trial involving 108 antiretroviral therapy-naive, incarcerated, HIV-infected persons, was conducted to evaluate a compact regimen (4 tablets per day) consisting of 1 lamivudine-zidovudine (150 mg/300 mg) combination tablet (COM) and one 300-mg abacavir tablet administered twice daily under directly observed treatment conditions. In the intent-to-treat observed analysis, the plasma HIV type 1 (HIV-1) RNA level remained at < or =400 copies/mL in 85% of the patients and at < 50 copies/mL in 75% of the patients. Median change from baseline was -2.41 log(10) copies/mL for the HIV-1 RNA level and +111 cells/mm(3) for the CD4 cell count. The overall adherence to prescribed doses was 94% for patients who remained enrolled in the study. COM-abacavir given twice daily was generally well tolerated, and adverse events prompted only 4 patients to withdraw from the study.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Therapy, Combination; Female; Health Care Costs; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Treatment Outcome; Zidovudine

Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to <400 copies/mL. Drug-related serious adverse events were reported by 7.7% of patients, the most common of which were nausea, skin rash, diarrhea, malaise or fatigue, and fever. Approximately 4.6% of patients experienced a hypersensitivity reaction that was possibly drug related. Overall, the types and incidences of adverse events reported in the abacavir EAP were similar to those reported in phase 2 and 3 clinical trials evaluating abacavir.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; Health Services Accessibility; HIV Infections; HIV-1; Humans; Male; Treatment Outcome

To assess the safety and efficacy of three new drugs in patients with antiretroviral failure and to correlate retrospectively baseline factors with virological response.. Open-label, 48-week, single-arm, multi-center phase II trial conducted at nine US university or government clinics and private practices.. Patients with HIV-1 RNA > or =500 copies/ml despite > or =20 weeks of treatment with at least one protease inhibitor received abacavir 300 mg twice a day, amprenavir 1200 mg twice a day and efavirenz 600 mg once a day. Other antiretrovirals were prohibited until week 16 except for substitutions for possible abacavir hypersensitivity.. HIV RNA at weeks 16 and 48.. A total of 101 highly treatment-experienced patients enrolled; 60 were naive to non-nucleoside analog reverse transcriptase inhibitors (NNRTI). HIV RNA < 400 copies/ml was attained in 25 out of 101 (25%) patients at 16 weeks (35% of NNRTI-naive and 10% of -experienced patients) and 23 (23%) patients at 48 weeks (33% of naive and 7% of experienced patients). CD4 cells increased by a median of 15 x 10(6) and 43 x 10(6) cells/l at weeks 16 and 48, respectively. Drug-related rash occurred in 50 out of 99 (51%) of patients, and 17 out of 99 (17%) permanently discontinued one or more drugs as a result. Lower baseline viral load, fewer NNRTI-related mutations, absence of decreased abacavir (> or =4-fold) and efavirenz (> or =10-fold) susceptibility, and greater number of drugs to which virus was susceptible were associated with virological response at week 16.. Abacavir, amprenavir and efavirenz durably reduced HIV RNA and increased CD4 cell counts in a subset of treatment-experienced adults. Baseline viral load and some genotypic and phenotypic markers of resistance correlated with HIV RNA response.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Female; Furans; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Phenotype; Retrospective Studies; RNA, Viral; Safety; Sulfonamides; Treatment Failure

Highly active antiretroviral therapy (HAART) of HIV disease is associated with effective virologic control, immune reconstitution, and clinical improvements. This study addresses the potential for improvements in lymphocyte phenotype and virologic responses of HIV-infected persons with extensive experience with dual nucleoside reverse transcriptase (NRTI) treatment and advanced HIV disease after a change to a potent antiretroviral therapy (NRTI + protease inhibitor). The majority of participants achieved virologic success. There was a median rise in CD4+ lymphocytes of 99 cells/mm(3) by 48 weeks, because of an increase in memory CD4+ cells at 4 and 16 weeks, followed by a later increase in naive CD4+ cells between weeks 16 and 48. The proportion of activated, DR+ CD38+ CD8+ lymphocytes decreased during the 48 weeks of follow-up. The immunologic findings (increased memory and naive T cells and reduced activation levels) were significantly improved in participants with persistent suppression of viral replication over the 48 weeks of the study. Baseline HIV RNA copy number was lower (median, 14,784 copies/ml) in persons who responded virologically than in those not suppressing viral replication (median, 49,454 copies/ml). CD4+ cell counts above the median (125/mm(3)) at time 0 for the participants, was the only baseline immunologic marker significantly associated with viral suppression at week 48. Participants older than 40 years of age demonstrated less immunologic recovery. The results of the study show that patients with extensive experience with NRTIs respond both virologically and immunologically during the first 48 weeks of therapy with a potent antiretroviral regimen.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cyclopropanes; Didanosine; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dual-nucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1.. In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptom-free (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat.. Children had a median CD4 percentage of 22% (IQR 15-29) and a mean HIV-1 RNA concentration of 5.0 log copies/mL (SD 0.8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1.71, 2.19, and 2.63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0.02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events--six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir.. Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine

Topics: AIDS Vaccines; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Defective Viruses; Dideoxynucleosides; Furans; HIV Infections; Humans; Immunotherapy, Active; Lamivudine; Lymphocyte Count; Sulfonamides; T-Lymphocyte Subsets; Vaccination; Vaccinia virus; Viral Load; Viral Vaccines; Viremia; Zidovudine

Topics: Adult; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Male

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Male

Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge.. To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen.. Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks.. Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.. A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL.. Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil.. Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility.. Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03).. In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Disease Progression; Double-Blind Method; Drug Resistance, Viral; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nelfinavir; Organophosphonates; Oxazines; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Saquinavir; Sulfonamides; Treatment Failure; Viral Load

Peripheral lipoatrophy may complicate antiretroviral therapy of human immunodeficiency virus (HIV) infection, often related to duration and type of nucleoside analog therapy, and may have a mitochondrial pathogenesis. No proven therapy exists for lipoatrophy, but abacavir is a nucleoside analog that may be less toxic to mitochondria.. To determine if substitution of stavudine or zidovudine with abacavir improves HIV lipoatrophy without affecting control of HIV replication.. Randomized, open-label 24-week study.. Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001.. A total of 111 adults (109 men) with moderate or severe lipoatrophy who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy.. Patients were randomly assigned to switch from stavudine or zidovudine to abacavir, 300 mg twice per day, while continuing all other antiretroviral therapy (n = 54) or to continue all antiretroviral therapy (n = 57).. The primary end point was limb fat mass, measured by dual-energy x-ray absorptiometry; key secondary end points were plasma HIV RNA levels, adverse events, physician-assessed (via subjective measures) lipodystrophy severity, total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate) levels.. There was a significant increase in limb fat in the abacavir group relative to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31; 95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative increases in subcutaneous thigh (P =.01), arm (P<.001), and abdominal (P =.001) fat areas on computed tomography. Switching had no significant effect on secondary end points, including plasma HIV RNA (for unadjusted comparison between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in limb fat mass at week 24 did not correlate with change in subjectively determined perceived lipoatrophy severity (r = -0.06; P =.53 by Spearman correlation). Hypersensitivity to abacavir was seen in 5 patients (10%).. In this sample of lipoatrophic HIV-infected adults, switching from stavudine or zidovudine to abacavir for 24 weeks led to significant, albeit modest, objectively measured increases in limb fat. Clinical lipoatrophy, as assessed subjectively, did not resolve, however, and at the rate of increase observed may take years to resolve with use of this strategy. Longer-term follow-up is needed.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Body Composition; Dideoxynucleosides; Female; HIV Infections; Humans; Lipids; Lipodystrophy; Male; Middle Aged; Quality of Life; Reverse Transcriptase Inhibitors; Stavudine; Tomography, X-Ray Computed; Treatment Outcome; Viral Load; Zidovudine

This open-label, multicenter, single-arm clinical trial assessed the 48-week efficacy of a twice-daily triple nucleoside reverse-transcriptase inhibitor regimen containing a lamivudine (150 mg)-zidovudine (300 mg) combination tablet (COM) and abacavir (ABC; 300 mg) in 87 antiretroviral therapy-experienced, protease inhibitor-naive patients infected with human immunodeficiency virus type 1 (HIV-1). At baseline, the median plasma HIV-1 RNA level was 3.10 log(10) copies/mL, and the median CD4 cell count was 506 cells/mm(3). An intent-to-treat&rcolon;observed analysis showed that, at weeks 24 and 48 of treatment, HIV-1 RNA level was <400 copies/mL in 48 (76%) of 63 and 45 (82%) of 55 patients, respectively, and <50 copies/mL in 37 (59%) of 63 and 31 (56%) of 55 patients, respectively. Previous zidovudine or lamivudine use and presence at baseline of the M184V reverse-transcriptase mutation did not impact virologic response. Median CD4 cell counts were maintained above baseline throughout the study. COM plus ABC was generally well tolerated.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment.. To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen.. A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe.. Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L.. Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy.. Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48.. The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment.. In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Microbial; Female; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Indinavir; Lamivudine; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; Survival Analysis; Therapeutic Equivalency; Viral Load; Zidovudine

This article discusses the design of an ongoing open-label, randomized trial comparing three strategies of initial and subsequent HIV therapy in terms of long-term immunological and virological effect. The three treatment arms are (1) didanosine (ddI) plus stavudine (d4T) plus efavirenz (EFV) followed by zidovudine (ZDV) plus lamivudine (3TC) plus abacavir (ABC) plus nelfinavir (NFV); (2) ddI plus d4T plus NFV followed by ZDV plus 3TC plus ABC plus EFV; (3) ddI plus d4T plus EFV plus NFV followed by ZDV plus 3TC plus ABC plus saquinavir plus ritonavir. The primary objective is to determine whether it is best to start with a protease inhibitor (PI)-containing regimen, a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI)-containing regimen, or with a regimen containing both a PI and an NNRTI. The aim is to recruit over 1000 patients followed for at least 3 years. The entry criteria are broad with no restriction on stage of disease, CD4 count, or HIV viral load. The criteria for therapeutic failure determining change of treatment are not defined and are left to the clinicians, but randomization is stratified by country and by the current criteria used for changing treatment. We describe the rationale behind various aspects of the design and discuss the complexities involved in undertaking such a large trial in HIV-infected patients from 180 clinical sites in 17 countries. Control Clin Trials 2001;22:160-175

Topics: Adult; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Selection; Randomized Controlled Trials as Topic; Research Design; Ritonavir; Sample Size; Saquinavir; Stavudine; Zidovudine

To investigate the steady-state pharmacokinetics of a triple combination tablet containing abacavir (ABC) 300 mg, lamivudine (3TC) 150 mg, and zidovudine (ZDV) 300 mg taken twice/day, and those of ABC 300 mg twice/day plus a double combination tablet containing 3TC 150 mg and ZDV 300 mg twice/day (ABC-COM).. Open-label, crossover study.. Two hospital-based clinical research units.. Twelve men infected with human immunodeficiency virus-1.. Steady-state pharmacokinetics of ABC, 3TC, and ZDV were assessed after dosing with ABC-COM and the triple combination tablet.. Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar for the triple combination tablet versus ABC-COM for the following: geometric mean (GM) area under the serum concentration-time curve, ABC 6.08 versus 5.87, 3TC 5.51 versus 5.53, and ZDV 1.38 versus 1.46 microg x hr/ml; GM maximum serum concentration (Cmax-ss), ABC 3.09 versus 3.19, 3TC 1.26 versus 1.40, and ZDV 1.19 versus 1.15 microg/ml; median time to Cmax-ss, ABC 0.75 versus 0.75, 3TC 1.50 versus 1.24, and ZDV 0.75 versus 0.75 hours; and GM oral clearance, ABC 51 versus 49, 3TC 27 versus 27, and ZDV 217 versus 206 L/hour. The GM half-lives of ABC and ZDV were similar for both treatments, 1.69 versus 1.58 and 2.30 versus 2.08 hours, respectively.. Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar in patients who took them as ABC-COM or as a triple combination tablet.

Topics: Adult; Area Under Curve; Cross-Over Studies; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Half-Life; HIV Infections; HIV-1; Humans; Lamivudine; Male; Metabolic Clearance Rate; Reverse Transcriptase Inhibitors; Tablets; Zidovudine

A Phase II clinical trial was designed to evaluate the efficacy and tolerability of twice-daily abacavir, amprenavir, and zidovudine (ZDV)/lamivudine (3TC) in HIV-1-infected study subjects naive to protease inhibitors and 3TC. Plasma and cerebrospinal fluid (CSF) HIV-1 RNA levels and T-cell subsets were measured. In all, 27 newly diagnosed and 12 chronically HIV-1-infected study subjects are included in the analysis. Week 48 plasma HIV-1 RNA levels were <500 copies/ml in 100% of study subjects, and <50 copies/ml in 80% of chronically infected and 100% of newly infected study subjects. The mean change in CD4 was (+)150 cells/microl (newly infected, p <.001), and (+)155 cells/microl (chronically infected, p <.001). At Week 48, evidence of cellular activation persisted in both cohorts. A twice-daily regimen of amprenavir, abacavir, and ZDV/3TC affords potent viral suppression and significant increases in total CD4(+) cells in HIV-1--infected study subjects. Patient intolerance may limit the efficacy of this combination.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS Dementia Complex; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chronic Disease; Dideoxynucleosides; Digestive System; Drug Synergism; Ethnicity; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocyte Subsets; Male; Pregnancy; Research Design; RNA, Viral; Sulfonamides; Treatment Refusal; Zidovudine

To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors.. A 48-week, open-label study.. Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count > or = 100 cells/mm3, plasma HIV-1 RNA > or = 5,000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA < or = 400 and < or = 50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities.. At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA < or = 400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA < or = 50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups.. Abacavir is safe and effective when used in combination with a protease inhibitor.

Topics: Administration, Oral; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; RNA, Viral; Time Factors

To demonstrate that lamivudine and zidovudine, given separately (lamivudine/zidovudine) or as a single combination tablet (Combivir), had equivalent efficacy. To evaluate the safety and antiretroviral activity of intensification with abacavir in patients treated with lamivudine/zidovudine for > or = 12 weeks.. A 12-week, equivalence study of lamivudine/ zidovudine versus Combivir. Patients who completed this study could enter a 48-week, intensification study of Combivir plus abacavir.. In the equivalence study, treatment-naive patients were assessed for HIV-1 RNA, CD4 cell count and genotype. The same assessments plus phenotype were made in the intensification study. Serious adverse events were recorded in the equivalence study and all adverse events in the intensification study.. Lamivudine/zidovudine (n=40) and Combivir (n=35) gave equivalent reductions in plasma HIV-1 RNA levels at week 12. An identical proportion of patients (74%) in each treatment group harboured virus with the M184V mutation after 12 weeks. Fifty-two patients entered the intensification study and 44 completed 48 weeks of treatment. At the time of intensification with abacavir, all 35 patients with evaluable isolates harboured HIV-1 containing M184V. Addition of abacavir to Combivir led to further decreases in plasma HIV-1 RNA and increases in CD4 cell counts compared with the start of intensification (P<0.001 at week 48). After 48 weeks of triple therapy, multi-nucleoside resistance mutations at codons 69 and 151 were not detected in any patients. All treatment regimens were generally well tolerated.. Lamivudine/zidovudine and Combivir have equivalent antiretroviral activity over 12 weeks. Adding abacavir to Combivir can be a safe and effective therapeutic option for patients, including those harbouring virus with the M184V mutation.

Topics: Administration, Oral; Adolescent; Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Time Factors; Zidovudine

To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults.. Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial.. Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively.. At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy.. The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Maximum Tolerated Dose; Phenotype; Sulfonamides; Time Factors; Treatment Outcome

To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination.. In an open-label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment (n = 106). Clinical assessments included plasma HIV-1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self-report.. A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03). Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P < 0.001 andP = 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm.. The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing.

Topics: Adult; Aged; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Sequencing of reverse-transcriptase genes and recombinant virus assays were performed on paired isolates from antiretroviral drug-naive patients randomized to stavudine and didanosine (group 1; n = 21) or zidovudine and lamivudine (group 2; n = 21) at baseline and after > or = 12 months of follow-up. The T215Y mutation emerged in 13 (61.9%) and 2 (9.5%) isolates in groups 1 and 2, respectively (P < .0001). Furthermore, in group 1, mutations associated with multidideoxynucleoside resistance were selected in 3 isolates. In group 2, all isolates carried the M184V mutation. The median fold changes in susceptibilities to zidovudine, stavudine, and lamivudine were 16.4 and 1, 2.2 and 0.6, and 4.5 and > 38 in groups 1 and 2, respectively (P < .0001, all comparisons). These results suggest that the combination of stavudine and didanosine is associated more frequently with the emergence of zidovudine resistance and a decrease in susceptibility to stavudine than the combination of zidovudine and lamivudine.

Topics: Adult; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Microbial Sensitivity Tests; Phenotype; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Abacavir is a potent, novel 2'-deoxyguanosine analogue reverse transcriptase inhibitor (NRTI) which effectively suppresses HIV-1 replication. To date, there is no pharmacokinetic study in patients with renal impairment.. Five HIV-1-infected patients with various degrees of renal dysfunction (creatinine clearance 60, 40, 25, 20 and 1 haemodialyzed patient) were evaluated after being treated for at least 2 months with multi-antiretroviral therapy including abacavir. After an overnight fast, the subjects received their abacavir dosage (600 or 300 mg). Blood samples were withdrawn and plasma concentrations determined. A nonparametric pharmacokinetic analysis was then performed. The dialysability of abacavir was also evaluated.. Time of maximum plasma concentration (T(max)) was constant among the subjects with a mean value of 0.7 +/- 0.27 h (range 0.33-1). Maximum plasma concentration (C(max)) ranged from 2.76 to 4.15 mg/l (mean 3.44 +/- 0.59). The elimination half-life ranged from 1.31 to 2.67 h (mean 2.08 +/- 0.51). Normalized C(max)/dose ranged from 0.007 to 0.014 mg/l and normalized AUC(0-inf)/dose ranged from 0.014 to 0.035 mg.h/l. In haemodialysis the dialysance was 60-80 ml/min with a fractional drug removal of 24% during a 4-hour haemodialysis session with a high permeability membrane.. In our patients, absorption, elimination and distribution phases were not altered by renal insufficiency. Furthermore, our pharmacokinetic data are similar to those obtained in patients with normal renal function. Therefore, dosage adjustment is not necessary in patients with renal insufficiency. In haemodialyzed patients, treatment can be administered independently to the dialysis session because of the negligible elimination of abacavir in the dialysate.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Lipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution.. Eighty-one HIV protease inhibitor recipients (78 male; mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48.. There was a greater decline in total body fat in the switch group than in the continue group (-1.6 and -0.4 kg, respectively at week 24; P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter.. In predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Carnitine; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Organophosphonates; Quality of Life; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Treatment for HIV-1 infection is complicated by fat redistribution (lipodystrophy). This is associated with insulin resistance concerning glucose uptake. Our aim was to characterize glucose metabolism more comprehensively in HIV-1-infected patients with lipodystrophy. We assessed glucose disposal and its pathways, glucose production, plasma free fatty acid (FFA) levels, and the degree to which these parameters could be suppressed by insulin.. Six HIV-1-infected men on protease inhibitor-based HAART with lipodystrophy (HIV+LD) were studied. The results were compared with those in six matched healthy male volunteers. Insulin sensitivity was quantified by hyperinsulinemic euglycaemic clamp. Glucose production and uptake were assessed by tracer dilution employing 6,6D(2)-glucose.. At post-absorptive insulin concentrations, glucose production was 47% higher in HIV+LD than controls (P = 0.025). During clamp, glucose production was suppressed by 53% in HIV+LD, but by 85% in controls (P = 0.004). Glucose disposal increased in both groups, but by only 27% in HIV+LD versus 201% in controls (P = 0.004). Consequently, insulin-stimulated total glucose disposal was lower in HIV+LD patients (P = 0.006). Non-oxidative glucose disposal as percentage of total disposal did not differ significantly between groups (63% in HIV+LD and 62% in controls). Baseline plasma FFA concentrations were higher (0.60 versus 0.35 mmol/l; P = 0.024), whereas FFA decline during hyperinsulinemia was less (65 versus 85%; P = 0.01) in HIV+LD versus controls.. Post-absorptive glucose production is increased in HIV-1-infected patients with lipodystrophy. Moreover, both the ability of insulin to suppress endogenous glucose production and lipolysis, and to stimulate peripheral glucose uptake and its metabolic pathways is reduced, indicating severe resistance concerning multiple effects of insulin.

Topics: Adult; Anti-HIV Agents; Body Composition; Dideoxynucleosides; Drug Therapy, Combination; Fatty Acids; Glucose; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Reverse Transcriptase Inhibitors

To evaluate antiretroviral efficacy of abacavir (ABC) in antiretroviral-experienced patients, by intensifying current antiretroviral therapy (CART) in patients with stable, detectable plasma HIV-1 RNA.. Thirty-two European centres recruited HIV-1 positive patients with < or = 36 months of CART experience. Patients were randomized to receive either ABC (300 mg twice daily) plus CART (ABC + CART) or ABC placebo plus CART (CART). We assessed efficacy as measured by plasma HIV-1 RNA and CD4+ cell counts and safety at baseline, weeks 2, 4 and every 4 weeks thereafter until week 48. Protocol-defined criteria enabled patients to switch to open-label ABC from week 8 onwards.. Ninety-two patients with a median plasma of 3.66 log10 HIV-1 RNA copies/mL and a median CD4+ cell count of 408 cells/microL were randomized to ABC + CART and 93 patients with a median plasma of 3.52 log10 HIV-1 RNA copies/mL and a median CD4+ cell count of 411 cells/microL were randomized to CART. From weeks 8-48, 11 (12%) patients in the ABC + CART group and 34 (37%) patients in the CART group switched to open-label ABC. At week 48, significantly more patients on ABC + CART (23/92, 25%) than on CART (5/93, 5%) had plasma < or =400 HIV-1 RNA copies/mL (P < 0.001, intent-to-treat switch = failure population). Neither duration of previous nucleoside reverse transcriptase inhibitor treatment (up to 18 months) nor prior lamivudine therapy affected ABC efficacy. In the ABC + CART group, 16/25 (64%) patients with the M184V mutation at baseline had < or = 400 copies/mL or a decrease > or = 1 log10 copies/mL at week 16. More patients (19/46, 41%) with baseline viral load < or = 5000 copies/mL had plasma < 400 HIV-1 RNA copies/mL at 48 weeks than those > 5000 copies/mL (4/44, 9%). CD4+ cell counts increased by 102 cells/microL and 57 cells/microL at week 48 for the ABC + CART and CART groups, respectively (intent-to-treat, switch included). ABC addition had minimal impact on the CART safety profile.. ABC intensification, in CART-experienced patients with low viral loads and limited reverse transcriptase mutations, most of whom had previously been on double-therapy, resulted in a significant and durable plasma HIV-1 reduction and concomitant increase in CD4+ cell count. The presence of M184V at baseline had minimal impact on the efficacy of ABC.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Synergism; Europe; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR).. Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR.. Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51).. The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

Topics: Adult; Anti-HIV Agents; Anti-Inflammatory Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Prednisolone; Reverse Transcriptase Inhibitors

Patients with plasma viral RNA >50,000 copies/mL, despite a protease-inhibitor regimen, received abacavir, amprenavir, and efavirenz to assess efavirenz-amprenavir drug interactions and to evaluate safety and antiviral response. Patients first received amprenavir with abacavir and other nucleoside analogs. Amprenavir levels were measured before and after adding efavirenz. Patients then received a second protease inhibitor. There was evidence of genotypic and phenotypic resistance at study entry. No patient had study drugs discontinued because of toxicity. Efavirenz decreased the steady-state area under the curve, maximum plasma concentration, and minimum plasma concentration of amprenavir by 24%, 33%, and 43%, respectively. Three of 10 patients had >1.5 log10 viral response to abacavir and amprenavir. All 8 patients who added efavirenz had >0.5 log10 decline in viral load, and this response lasted >24 weeks for 3 of the patients. A combination regimen that included abacavir, amprenavir, and efavirenz was well tolerated and had sustained activity in some patients. Concomitant efavirenz therapy decreases amprenavir concentrations.

Topics: Adult; Alkynes; Antiviral Agents; Area Under Curve; Base Sequence; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Furans; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Oxazines; Phenotype; Pilot Projects; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

To examine changes in HIV-1 susceptibility (genotype and phenotype) during an initial abacavir monotherapy phase followed by the addition of zidovudine and lamivudine.. Sixty HIV-1 infected, antiretroviral therapy-naive subjects were randomized to receive 100, 300 or 600 mg abacavir twice daily. Subjects completing 24 weeks of randomized therapy or meeting a protocol defined switch criterion could switch to open label abacavir/zidovudine/lamivudine.. Plasma HIV-1 reverse transcriptase was genotyped at baseline, week 12, and at the last time point on ABC monotherapy. Drug susceptibility was analysed at baseline and on subsequent samples with sufficient HIV-1 RNA levels using the recombinant virus assay. Virological responses (week 24) were correlated to week 24 genotypes.. Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, weeks 6-48), 21 out of 43 subjects harboured virus with resistance conferring mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/21 cases). Twenty of the 21 subjects with isolates containing abacavir-associated mutations reached week 48, and upon addition of lamivudine/zidovudiine, 16 out of 20 (80%) had week 48 plasma HIV-1 -RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/or Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log10 copies/ml or -1.99 log10 copies reduction from baseline). Genotype correlated well with phenotypic resistance to ABC; four samples with three abacavir-associated mutations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All samples with single mutations retained full ABC susceptibility.. Resistance conferring mutations to abacavir were relatively slow to develop during the monotherapy phase, and did not preclude durable efficacy of abacavir/lamivudine/zidovudine up to 48 weeks.

Topics: Cohort Studies; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Phenotype; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Zidovudine

The long-term kinetics of T cell production following highly active antiretroviral therapy (HAART) were investigated in blood and lymph node in a group of HIV-infected subjects at early stage of established infection and prospectively studied for 72 wk. Before HAART, CD4 and CD8 T cell turnover was increased. However, the total number of proliferating CD4(+) T lymphocytes, i.e., CD4(+)Ki67(+) T lymphocytes, was not significantly different in HIV-infected (n = 73) and HIV-negative (n = 15) subjects, whereas proliferating CD8(+)Ki67(+) T lymphocytes were significantly higher in HIV-infected subjects. After HAART, the total body number of proliferating CD4(+)Ki67(+) T lymphocytes increased over time and was associated with an increase of both naive and memory CD4(+) T cells. The maximal increase (2-fold) was observed at week 36, whereas at week 72 the number of proliferating CD4(+) T cells dropped to baseline levels, i.e., before HAART. The kinetics of the fraction of proliferating CD4 and CD8 T cells were significantly correlated with the changes in the total body number of these T cell subsets. These results demonstrate a direct relationship between ex vivo measures of T cell production and quantitative changes in total body T lymphocyte populations. This study provides advances in the delineation of the kinetics of T cell production in HIV infection in the presence and/or in the absence of HAART.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV Seronegativity; Humans; Kinetics; Lymph Nodes; Lymphocyte Activation; Middle Aged; Nelfinavir; Regression Analysis; Saquinavir; T-Lymphocyte Subsets; T-Lymphocytes; Time Factors

While in vitro results at clinically relevant concentrations do not predict abacavir (1592U89) interactions with drugs highly metabolized by cytochrome P450, the potential does exist for a pharmacokinetic interaction between abacavir and ethanol, as both are metabolized by alcohol dehydrogenase. Twenty-five subjects were enrolled in an open-label, randomized, three-way-crossover, phase I study of human immunodeficiency virus-infected male subjects. The three treatments were administration of (i) 600 mg of abacavir, (ii) 0.7 g of ethanol per kg of body weight, and (iii) 600 mg of abacavir and 0.7 g of ethanol per kg. Twenty-four subjects completed the study with no unexpected adverse events reported. Ethanol pharmacokinetic parameters were unchanged with abacavir coadministration. The geometric least squares mean area under the concentration curve extrapolated to infinite time for abacavir increased 41% (from 11.07 to 15.62 microg. h/ml), and the half-life increased 26% (from 1.42 to 1.79 h) in the presence of ethanol (mean ethanol maximum concentration in plasma of 498 microg/ml). The percentages of abacavir dose recovered in urine as abacavir and its two major metabolites were each altered in the presence of ethanol, but there was no change in the total percentage ( approximately 50%) of administered dose recovered in the 12-h collection interval. In conclusion, while a single 600-mg dose of abacavir does not alter blood ethanol concentration, ethanol does increase plasma abacavir concentrations.

Topics: Adolescent; Adult; Anti-Infective Agents, Local; Dideoxynucleosides; Drug Interactions; Ethanol; HIV Infections; Humans; Male; Middle Aged

To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA < or = 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks.. One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts > or = 100 x 10(6)/l and plasma HIV-1 RNA of 400-50,000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study.. Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses.. At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA < or = 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%; P < 0.001). A similar response was observed in both the lamivudine naive and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a > or = 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of < or = 400 copies/ml by week 16.. ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.

Topics: Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Phenotype; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load

Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4(+) cell counts of >/=100/mm(3) and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse sampling were analyzed by standard population pharmacokinetic methods, and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter estimates were calculated to determine the peak concentration of abacavir in plasma (C(max)) and the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC(0-infinity). A significant correlation was observed between C(max) and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log(10) time-averaged AUC(0-infinity) minus baseline (AAUCMB) values for HIV-1 RNA and CD4(+) cell count correlated significantly with C(max) and AUC(0-infinity), but with better model fits for AUC(0-infinity). The increase in AAUCMB values for CD4(+) cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. There was less than a 0.4 log(10) difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC(0-infinity) from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.

Topics: Adolescent; Adult; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; RNA, Viral

Abacavir (1592U89) is a nucleoside reverse transcriptase inhibitor with potent activity against human immunodeficiency virus type 1 (HIV-1) when used alone or in combination with other antiretroviral agents. The present study was conducted to determine the multiple-dose pharmacokinetics and pharmacodynamics of abacavir in HIV-1-infected subjects following oral administration of daily doses that ranged from 600 to 1,800 mg, with and without zidovudine. Seventy-nine subjects received abacavir monotherapy for 4 weeks (200, 400, or 600 mg every 8 hours [TID] and 300 mg every 12 h [BID]) and thereafter received either zidovudine (200 mg TID or 300 mg BID) or matching placebo with abacavir for 8 additional weeks. Pharmacokinetic parameters were calculated for abacavir after administration of the first dose and at week 4 and for abacavir, zidovudine, and its glucuronide metabolite at week 12. The concentrations of abacavir in cerebrospinal fluid were determined in a subset of subjects. Steady-state plasma abacavir concentrations were achieved by week 4 of monotherapy and persisted to week 12. At steady state, abacavir pharmacokinetic parameters (area under the plasma concentration-time curve for a dosing interval [AUC(tau)] and peak concentration [C(max)]) were generally proportional to dose over the range of a 600- to 1,200-mg total daily dose. Coadministration of zidovudine with abacavir produced a small and inconsistent effect on abacavir pharmacokinetic parameters across the different doses. At the clinical abacavir dose (300 mg BID) zidovudine coadministration had no effect on the abacavir AUC(tau), which is most closely associated with efficacy. Zidovudine pharmacokinetics appeared to be unaffected by abacavir. Statistically significant but weak relationships were found for the change in the log(10) HIV-1 RNA load from the baseline to week 4 versus total daily AUC(tau) and C(tau) (P < 0.05). The incidence of nausea was significantly associated with total daily AUC(tau) and C(max). In conclusion, abacavir has predictable pharmacokinetic characteristics following the administration of multiple doses.

Topics: Adolescent; Adult; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Zidovudine

To evaluate the immunological and virological responses to highly active antiretroviral therapy (HAART) in blood and lymphoid compartments of HIV-1-infected patients at an early stage of infection.. An open-label, observational, non-randomized, prospective trial of outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.. Forty-one antiretroviral-naive HIV-1-infected adults with 400 CD4 T cells/microl or greater and 5000 plasma HIV-1-RNA copies/ml or greater were enrolled, and 32 finished the study. Forty-nine HIV-negative individuals were included as controls. All subjects gave written informed consent.. All patients received abacavir 300 mg by mouth every 12 h and amprenavir 1200 mg by mouth every 12 h for 72 weeks.. The extent of immune reconstitution in blood and lymph nodes after 72 weeks of HAART was evaluated, and compared with immunological measures of 49 HIV-negative subjects.. Virus replication was effectively suppressed (-3.5 log10 at week 72). Substantial increments of CD4 T cell count in blood and percentage in lymph nodes were observed over time, and these measures were comparable to HIV-negative subjects by week 24 in blood and by week 48 in lymph nodes. The increase was equally distributed between naive and memory CD4 T cells. Recovery of HIV-specific CD4 responses occurred in 40% of patients.. The initiation of HAART at an early stage of established HIV infection induces systemic quantitative normalization of CD4 T cells, a partial recovery of HIV-specific CD4 cell responses, and effective and durable suppression of virus replication.

Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Carbamates; CD4 Lymphocyte Count; CD4-CD8 Ratio; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lymph Nodes; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Sulfonamides; Viral Load

When to start highly active antiretroviral therapy (HAART) in asymptomatic chronically HIV-1-infected subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6)/l is debated extensively. Retrospective analyses of virological and immunological responses following HAART have been evaluated in both blood and lymph nodes according to pre-treatment levels of CD4 cells either above or below 500 x 10(6)/l.. Open-label, observational, non-randomized, prospective study.. Outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.. Fifty-four HIV-1-infected antiretroviral-naive subjects with CD4 cell count > or = 250 x 10(6)/l and plasma viraemia > or = 5000 copies/ml who had been treated with HAART for at least 48 weeks. Controls were 49 HIV-negative subjects.. All patients received abacavir, nelfinavir, saquinavir soft gel capsules, and amprenavir in varying combinations for 72 weeks.. The extent of immune reconstitution following HAART in 43 and 11 subjects with either more or fewer than 500 x 10(6) CD4 cells/l at baseline was evaluated in blood and lymph node, and compared with immunological measures observed in 49 HIV-negative controls.. After 48 weeks of therapy, plasma viraemia was suppressed effectively in both groups of patients. Normalization of both CD4 cell count in blood, divided equally between memory and naive cells, and percentage of CD4 cells in lymph nodes occurred in the two groups. Consistently, the net increase over baseline in CD4 cell count and in memory and naive CD4 subsets was greater in patients with fewer than 500 x 10(6) CD4 cells/l at baseline. Recovery of HIV-specific responses was similar in the two groups.. This study suggests that virological and immunological responses are comparable in asymptomatic therapy-naive HIV-1-infected subjects with CD4 cell counts above or below 500 x 10(6)/l.

Topics: Adult; Anti-HIV Agents; Antigens, Fungal; Antigens, Viral; Antiretroviral Therapy, Highly Active; Candida albicans; Carbamates; CD4 Lymphocyte Count; Chronic Disease; Cytomegalovirus; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nelfinavir; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Simplexvirus; Sulfonamides; T-Lymphocyte Subsets

To characterize early and later indices of cellular restoration among HIV-1 infected persons treated with abacavir and one protease inhibitor and to identify predictors of CD4 cell increases.. Flow-cytometric analyses of lymphocyte phenotypes among 71 antiretroviral treatment naive adults in a 48 week treatment trial.. During the first 4 weeks of therapy, increases in naive and memory CD4 cells and in B cells were seen; naive CD8 cells increased while CD8 cells remained stable as memory CD8 cells decreased. During the second phase total CD4 and naive CD4 and CD8 cells increased while total CD8 and memory CD8 cells decreased. The numbers of CD4 cells that expressed CD28 increased from a median of 308 x 10(6)/l at baseline to 477 x 10(6)/l at week 48. Higher baseline plasma HIV-1 RNA levels predicted the magnitude of early CD4 (r = 0.35; P = 0.01), memory CD4 (r = 0.38; P = 0.001) and CD28 CD4 cell (r = 0.29; P = 0.01) restoration but was not related to second phase changes. Younger age predicted a greater second phase (but not first phase) increase in naive CD4 cells (r = -0.31; P = 0.03).. Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.

Topics: Adolescent; Adult; Aged; Aging; Antigens, CD; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Therapy, Combination; Female; Flow Cytometry; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Immunophenotyping; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4+ cell counts ranging from < 50 to 713 cells per mm3 (median, 315 cells per mm3) were randomly assigned to receive abacavir (n = 12) or placebo (n = 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC50) for clinical HIV isolates in vitro (0.07 microgram/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 micrograms/ml for Cmax; from 1.0 to 15.7 micrograms.h/ml for AUC0-infinity) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 micrograms/ml for Cmax; from 15.7 to 32.8 micrograms.h/ml for AUC0-infinity. The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Dideoxynucleosides; Double-Blind Method; Female; Half-Life; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Spectrophotometry, Ultraviolet

Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog reverse transcriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase I study was conducted to evaluate the pharmacokinetics and safety of abacavir following the administration of two single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected children ages 3 months to 13 years. Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was rapidly absorbed, with the time to the peak concentration in plasma occurring within 1.5 h postdosing. Pharmacokinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (Cmax) and the mean area under the curve from time zero to infinity (AUC0-infinity) increased by 16 and 45% more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (Cmax increased from 1.69 to 3.94 micrograms/ml, and AUC0-infinity increased from 2.82 to 8.09 micrograms.h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. The mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the dose increased. Neither body surface area nor creatinine clearance were correlated with pharmacokinetic estimates at either dose. The extent of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight. In conclusion, this study showed that abacavir is safe and well tolerated in children when it is administered as a single oral dose of 4 or 8 mg/kg.

Topics: Adolescent; Area Under Curve; Child; Child, Preschool; Chromatography, High Pressure Liquid; Dideoxynucleosides; Double-Blind Method; Female; Half-Life; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Infant; Male; Reverse Transcriptase Inhibitors; Spectrophotometry, Ultraviolet

To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children.. HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4(+) lymphocyte counts, and plasma HIV RNA concentrations were evaluated.. At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4(+) lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy.. Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infant; Male; RNA, Viral

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

Topics: Adult; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; Nevirapine; Phenotype; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Salvage Therapy; Saquinavir

Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4(+) cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5'-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (Cmax), the area under the concentration-time curve from time zero to infinity (AUC0-infinity), time to Cmax (Tmax), and apparent elimination half-life (t1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the mean Cmax of ZDV by approximately 20% (from 1.5 to 1.2 microg/ml), delayed the median Tmax for ZDV by 0.5 h, increased the mean AUC0-infinity for GZDV by up to 40% (from 11.8 to 16.5 microg. h/ml), and delayed the median Tmax for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0-infinity for 3TC by approximately 15% (from 5.1 to 4.3 microg. h/ml), decreased the mean Cmax by approximately 35% (from 1.4 to 0.9 microg/ml), and delayed the median Tmax by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are relatively minor (for 3TC) and are therefore not considered to be clinically significant. No significant differences were found in the urinary recoveries of ZDV or GZDV when ZDV was coadministered with abacavir. There was no pharmacokinetic interaction between ZDV and 3TC. Mild to moderate headache, nausea, lymphadenopathy, hematuria, musculoskeletal chest pain, neck stiffness, and fever were the most common adverse events reported by those who received abacavir. Coadministrati

Topics: Adolescent; Adult; Anti-HIV Agents; Cross-Over Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Zidovudine

To establish the feasibility of using ultrasound-guided lymph node needle aspiration as a means to obtain lymphoid tissue cells for the determination of a series of immunologic and virologic measures in HIV-infected patients.. First, a comparison of the characteristics of cell populations obtained by simultaneous needle aspiration and standard excisional biopsy in six patients. Second, use of lymph node needle aspiration to assess longitudinally T-cell subset changes in patients initiating highly effective antiretroviral treatment.. T-cell subsets (CD4 and CD8) and percentage Ki67+ cycling T cells were measured in lymph node cell populations harvested by ultrasound-guided aspiration or standard biopsy by flow cytometry. Cellular RNA content was assessed by a modification of the Roche Amplicor HIV-1 Monitor test.. CD4 and CD8 T-cell percentage and HIV RNA cell content of lymph node cell suspensions obtained from the simultaneous performance of ultrasound-guided needle aspiration and excisional biopsy in the same patients were correlated (n = 6). Among the 87 aspiration sessions reported here, mononuclear cell suspensions were obtained in 100% of the sessions, in numbers ranging between 4x10(4) to 6.7x10(6) cells (median: 7x10(5)). This limited number of cells did not allow to perform all type of analyses in all patients. By prioritizing the cells for the determination of T-cell subsets and proliferation rate, this approach was instrumental for demonstrating the normalization of the T-cell subset ratio and the kinetic of normalization of proliferating rates of CD4 and CD8 T cells, as well as the decrease in HIV-1 viral load in the lymph node following HAART initiation.. Ultrasound-guided aspiration appears to be a non-invasive and ad libitum, safe and repeatable procedure for the longitudinal monitoring of changes in lymph nodes.

Topics: Anti-HIV Agents; Biopsy, Needle; Carbamates; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Therapy, Combination; Flow Cytometry; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Longitudinal Studies; Lymph Nodes; Lymphocyte Activation; Reverse Transcriptase Inhibitors; RNA, Viral; Sulfonamides; Ultrasonography

Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi of [(14)C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.

Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Dideoxynucleosides; Feces; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Spectrophotometry, Ultraviolet

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) are currently available for HIV patients.. This study evaluated modifications in the renal safety profile in a large real-world cohort of patients who had received EVG/c/FTC/TAF or DTG/ABC/3TC.. A retrospective observational study of HIV-infected patients who received EVG/c/FTC/TAF or DTG/ABC/3TC between March 2015 and June 2019 at a reference hospital in north-western Spain was conducted. Epidemiological, clinical, immunovirological data and information regarding antiretroviral therapy were recorded. The statistical differences between treatments were calculated.. A total of 457 patients were evaluated, 266 using EVG/c/FTC/TAF and 191 using DTG/ABC/3TC. Up to week 120, serum creatinine improved in both study groups among experienced patients (EVG/c/FTC/TAF 1.01±0.24 vs 0.91±0.19, p<0.001; DTG/ABC/3TC 1.08±0.24 vs 1.02±0.31, p<0.001), while in naïve patients serum creatinine remained stable compared with baseline. Statistically significant differences were found in serum creatinine when comparing both treatments at week 48 in experienced (0.94±0.21 vs 1.09±0.28, p<0.001) and naïve patients (0.89±0.16 vs 1.06±0.20, p=0.001), and among experienced patients at week 120 (0.91±0.19 vs 1.02±0.31, p=0.015) for the EVG/c/FTC/TAF and DTG/ABC/3TC groups, respectively. During the follow-up, 39 patients in EVG/c/FTC/TAF and 33 in DTG/ABC/3TC (p=0.449) discontinued treatment. The main reason for stopping treatment was adverse events, which were similar in both groups.. During the follow-up, patients experienced changes that were not clinically relevant in both treatment groups. Differences in renal events were not found.

Topics: Anti-HIV Agents; Cobicistat; Creatinine; Emtricitabine; Fumarates; HIV Infections; Humans; Lamivudine

Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people with HIV.. Multinational cohort collaboration.. RESPOND participants were followed from the latest of 1 January 2012 or cohort enrolment until the first of a CVD event (myocardial infarction, stroke, invasive cardiovascular procedure), last follow-up or 31 December 2019. Logistic regression examined the odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within the past 6 months) and risk of CVD with negative binomial regression models, adjusted for potential confounders.. Of 29 340 individuals, 34% recently used ABC. Compared with those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk [odds ratio 1.12 (95% confidence interval = 1.04-1.21)] and significantly lower for individuals at moderate, high or very high CVD risk [0.80 (0.72-0.88), 0.75 (0.64-0.87), 0.71 (0.56-0.90), respectively]. During 6.2 years of median follow-up (interquartile range; 3.87-7.52), there were 748 CVD events (incidence rate 4.7 of 1000 persons-years of follow up (4.3-5.0)]. The adjusted CVD incidence rate ratio was higher for individuals with recent ABC use [1.40 (1.20-1.64)] compared with individuals without, consistent across sensitivity analyses. The association did not differ according to estimated CVD (interaction P  = 0.56) or CKD ( P  = 0.98) risk strata.. Within RESPOND's contemporarily treated population, a significant association between CVD incidence and recent ABC use was confirmed and not explained by preferential ABC use in individuals at increased CVD or CKD risk.

Topics: Cardiovascular Diseases; Disease Progression; HIV Infections; Humans; Renal Insufficiency, Chronic; Risk Factors

Prospective investigations on the risk of cardiovascular disease among youth with perinatally acquired human immunodeficiency virus (PHIV) in sub-Saharan Africa are lacking.. A prospective observational cohort study was performed in 101 youth (aged 10-18 years) with PHIV and 97 who were human immunodeficiency virus (HIV) uninfected (HIV-), from 2017 to 2021 at the Joint Clinical Research Center in Uganda. Participants with PHIV were receiving antiretroviral therapy (ART) and had HIV-1 RNA levels ≤400 copies/mL. The common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and at 96 weeks. Groups were compared using unpaired t-test, and potential predictors of IMT and PWV were assessed using quantile regression.. Of the 198 participants recruited at baseline, 168 (89 with PHIV, 79 HIV-) had measurements at 96 weeks. The median age (interquartile range) age was 13 (11-15) years; 52% were female, and 85% had viral loads <50 copies/mL that remained undetectable at week 96. The baseline mean common carotid artery IMT was slightly higher in participants with PHIV compared with controls (P < .01), and PWV did not differ between groups (P = .08). At week 96, IMT decreased and PWV increased in the PHIV group (P ≤ .03); IMT increased in the HIV- group (P = .03), with no change in PWV (P = .92). In longitudinal analyses in those with PHIV, longer ART duration was associated with lower PWV (β = .008 [95% confidence interval, -.008 to .003]), and abacavir use with greater IMT (β = .043 [.012-.074]).. In healthy Ugandan youth with PHIV, virally suppressed by ART, the common carotid artery IMT did not progress over 2 years. Prolonged and early ART may prevent progression of subclinical vascular disease, while prolonged use of abacavir may increase it.

Topics: Adolescent; Carotid Intima-Media Thickness; Dideoxynucleosides; Female; HIV; HIV Infections; Humans; Male; Prospective Studies; Pulse Wave Analysis; Uganda; Vascular Diseases

To compare the impact of tenofovir alafenamide (TAF) on the slope of the estimated glomerular filtration rate (eGFR) with that of abacavir in Japanese patients living with HIV infection.. These findings suggest that renal function should be monitored carefully after the initiation of TAF in Japanese patients with HIV infection.

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Emtricitabine; HIV Infections; Humans; Kidney; Lamivudine; Retrospective Studies

This study aimed to evaluate the potential of uptake of the commonly used antiretroviral drugs (ARVDs) in South Africa (abacavir, nevirapine, and efavirenz) by vegetable plants (beetroot, spinach, and tomato) from contaminated soil culture. The study results showed that all the studied vegetables have the potential to take up abacavir, nevirapine, and efavirenz from contaminated soil, be absorbed by the root, and translocate them to the aerial part of the plants. The total percentage of ARVDs found in the individual plant was mainly attributed to abacavir which contributed 53% in beetroot and 48% in spinach, while efavirenz (42%) was the main contributor in tomato. Abacavir was found at high concentrations to a maximum of 40.21 μg/kg in the spinach root, 18.43 μg/kg in the spinach stem, and 6.77 μg/kg in the spinach soil, while efavirenz was the highest concentrations, up to 35.44 μg/kg in tomato leaves and 8.86 μg/kg in tomato fruits. Spinach roots accumulated more ARVDs than beetroot and tomato however, the concentrations were not statistically different. Hydrophobicity was the main effect on the linearity, accumulation, and translocation of ARVDs. This study advances knowledge on the fate of ARVDs in agroecosystems, particularly in plant root - ARVD interaction and the resulting potentially toxic effects on plants. These results suggest that the quality of water used for crop irrigation needs to be assessed prior to irrigation to avoid vegetable plant pollution as contaminated water results in the contaminants uptake by plants. This may lead to the transfer of pollutants to the edible crops parts of and thus be unintentionally consumed by humans. More studies need to be continuously conducted to evaluate ARVDs bioaccumulation and their mechanism of uptake by other vegetables. The use of the pot-plant system can be recommended because it closely relates to the agricultural world.

Topics: Bioaccumulation; Fruit; HIV Infections; Humans; Nevirapine; Soil; Soil Pollutants; Vegetables; Water; Water Pollution

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Heart Disease Risk Factors; HIV Infections; HIV Integrase Inhibitors; Humans; Integrase Inhibitors; Reverse Transcriptase Inhibitors; Risk Factors

The continuous release of antiretroviral drugs into the environmental has resulted in the interest to assess their occurrence in various environmental matrices. Their presence has led to antiretroviral drugs being considered the pollutants of concern due to their possible alterations of the ecosystem as well as the antiviral resistance that may develop upon their unintentional consumption. Therefore, in this work, solid phase extraction (SPE), ultrasonic extraction (UE), Soxhlet extration (SE) and liquid chromatography coupled to photodiode array detector (LC-PDA) methods have been optimized and validated. They were then applied for the simultaneous determination of abacavir, nevirapine and efavirenz antiretroviral drugs in wastewater, river water, sludge, soil and sediments. The percentage recoveries ranged from 71% to 112% for SPE, 88 - 108% for SE and 61 - 104% for UE. Good precision with a relative standard deviation less than 20% in all compounds for all methods was obtained. The LODs and LOQs ranged between 0.68 and 0.77 µg/L and 2.1-2.4 µg/L for SPE; 0.8-0.9 µg/kg and 2.3-2.8 µg/kg for SE and 1.6-2.8 µg/kg and 4.9 - 7.0 µg/kg for UE, respectively. The concentrations ranged from

Topics: Ecosystem; HIV Infections; Humans; Nevirapine; Rivers; Sewage; Soil; Solid Phase Extraction; Ultrasonics; Wastewater; Water; Water Pollutants, Chemical

There is ongoing debate as to whether abacavir (ABC) increases the risk for cardiovascular disease(CVD) in people living with HIV (PLHIV) and the mechanisms underlying this possible association. We recently showed that the use of an ABC-containing regimen was independently associated with increased thrombin generation (TG). In the present study, we aim to explore these findings further, by studying the mechanistical processes that underly the global thrombin generation test via thrombin dynamics analysis. Thrombin dynamics analysis can pinpoint the cause of increased thrombin generation associated with ABC-use either to the procoagulant prothrombin conversion pathway or the anticoagulant thrombin inactivation pathway. In this cross-sectional study, 208 virally suppressed PLHIV were included, of whom 94 were on a ABC-containing regimen, 92 on a tenofovir disoproxil fumarate (TDF)-containing regimen, and the remainder on other regimens. We used Calibrated Automated Thrombinography to measure thrombin generation and perform thrombin dynamics analysis. The total amount of prothrombin conversion, as well as the maximum rate of prothrombin conversion were significantly increased in PLHIV on an ABC containing regimen compared to other treatment regimens. The levels of pro- and anticoagulant factors were comparable, indicating that the ABC-induced changes affect the kinetics of prothrombin conversion rather than procoagulant factor levels. Moreover, Von Willebrand Factor (VWF), active VWF and VWF pro-peptide levels were significantly higher in PLHIV than controls without HIV. However, they did not differ between ABC and non-ABC treated participants.

Topics: Anticoagulants; Cross-Sectional Studies; HIV Infections; Humans; Prothrombin; Thrombin; von Willebrand Factor

People living with HIV (PLHIV) are at increased risk for coronary artery disease (CAD). This study aimed to describe the features associated with CAD in PLHIV.. A case ([n =160] PLHIV with CAD) control ([n =317] PLHIV matched by age and sex without CAD) study was performed at the Alfred Hospital, Melbourne, Australia (January 1996 and December 2018). Data collected included CAD risk factors, duration of HIV infection, nadir and at-event CD4+ T-cell counts, CD4:CD8 ratio, HIV viral load, and antiretroviral therapy exposure.. Participants were predominantly male (n =465 [97.4%]), with a mean age of 53years. Traditional risk factors associated with CAD in univariate analysis included hypertension (OR 11.4 [95%CI 5.01, 26.33], P <0.001), current cigarette smoking (OR 2.5 [95% CI 1.22, 5.09], P =0.012), and lower high-density lipoprotein cholesterol (OR 0.14 [95%CI 0.05, 0.37], P <0.001). There was no association between duration of HIV infection, nadir or current CD4 cell count. However, current and ever exposure to abacavir (cases: 55 [34.4%]; controls: 79 [24.9%], P =0.023 and cases: 92 [57.5%]; controls: 154 [48.6%], P =0.048, respectively) was associated with CAD. In conditional logistic regression analysis, current abacavir use, current smoking, and hypertension remained significantly associated (aOR=1.87 [CI=1.14, 3.07], aOR=2.31 [1.32, 4.04], and aOR=10.30 [5.25, 20.20] respectively).. Traditional cardiovascular risk factors and exposure to abacavir were associated with CAD in PLHIV. This study highlights that aggressive management of cardiovascular risk factors remains critical for reducing risk in PLHIV.

Topics: Coronary Artery Disease; Female; HIV Infections; Humans; Hypertension; Male; Middle Aged; Risk Factors

The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands.. Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets.. Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed.. Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; HIV Infections; Humans; Infant; Kenya; Uganda

Herein, a simple spectrophotometric method coupled with chemometric techniques i.e. partial least square (PLS) and genetic algorithm (GA) were utilized for the simultaneous determination of the vital ternary antiretroviral therapy dolutegravir (DTG), lamivudine (LMV), and abacavir (ACV) in their combined dosage form. Calibration (25 samples) and validation (13 samples) sets were prepared for these drugs at different concentrations via implementing partial factorial experimental designs. The zero order UV spectra of calibration and validation sets were measured and then subjected for further chemometric analysis. Partial least squares with/without variable selection procedures i.e. genetic algorithm (GA) were utilized to untangle the UV spectral overlapping of these mixtures. Cross-validation and external validation methods were applied to compare the performance of these chemometric techniques in terms of accuracy and predictive abilities. It was found that six latent variables were optimum for modelling DTG, four latent variables for modelling LMV and three latent variables for modelling ACV. Although, good recoveries with prompt predictive ability were attained by these PLS, GA-PLS showed better analytical performance owing to its capability to remove redundant variables i.e. the number of absorbance variables have been reduced to about 21-29%. The proposed chemometric methods can be reliably applied for simultaneous determination of DTG, LMV, and ACV in their laboratory prepared mixtures and pharmaceutical preparation posing these chemometric methods as worthy and substantial analytical tools in in-process testing and quality control analysis of many antiretroviral pharmaceutical preparations.

Topics: Calibration; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Least-Squares Analysis; Oxazines; Piperazines; Pyridones; Spectrophotometry; Spectrophotometry, Ultraviolet

Topics: Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Topics: Alanine; Amides; Anti-HIV Agents; Dideoxynucleosides; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tenofovir; Weight Gain

No evidence-based optimal dosing guidance is available for abacavir liquid formulation use from birth. We used abacavir pharmacokinetic data from neonates and infants to determine an exact abacavir dosing strategy (mg/kg) for infants aged 0-3 months and to propose dosing by WHO weight band for neonates.. Abacavir pharmacokinetic and safety data were pooled from three completed studies (1997-2020): PACTG 321 (USA), the Tygerberg Cohort (South Africa), and IMPAACT P1106 (South Africa). PACTG 321 and the Tygerberg Cohort were performed in neonates exposed to HIV receiving a single dose of abacavir. IMPAACT P1106 included predominantly low birthweight (<2500 g) infants on antiretroviral therapy enrolled when they were younger than 3 months. We developed a population pharmacokinetic model and performed simulations to achieve abacavir exposures (area under the curve for 0-12 h) within the target range of 3·2-25·2 μg·h/mL, previously reported in older children.. 45 infants contributed 308 abacavir concentrations; 21 neonates were younger than 15 days. At first pharmacokinetic assessment, median postnatal age for PACTG 321 was 1 day and median bodyweight was 3·1 kg; for the Tygerberg Cohort it was 10 days and 3·3 kg; and for IMPAACT P1106 it was 73 days and 3·8 kg. Our model predicted a slow abacavir clearance of 2·51 mL/min per kg at birth, which doubled by 4 weeks of age. Therapeutic targets were achieved with exact abacavir doses of 2·0 mg/kg twice daily from 0 weeks to 4 weeks and 4·0 mg/kg twice daily from 4 weeks to 12 weeks. A fixed weight-band dosing strategy of 8 mg (for 2-3 kg), 10 mg (3-4 kg), and 12 mg (4-5 kg) abacavir twice daily achieved target exposures throughout the first 4 weeks of life without the need for dose adjustment due to age or bodyweight changes. No adverse events of grade 3 or higher were related to abacavir.. Integration of these dosing strategies into national and international guidelines for the abacavir liquid formulation will expand antiretroviral options from birth and simplify the clinical management of neonates with HIV.. National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, and the Collaborative Initiative for Paediatric HIV Education and Research Programme.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Child; Dideoxynucleosides; HIV Infections; Humans; Infant; Infant, Newborn

Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an antiretroviral therapy (ART) that included abacavir (ABC+) in comparison with PWH on ART without abacavir (ABC-), and with HIV seronegative (HIV-) individuals.. The 115 participants (63% men), aged 30-50 years, did not have CVD, metabolic, endocrine, or chronic renal conditions. PWH were on stable ART for six-months or more. Vascular assessments included flow-mediated dilation (FMD), aortic, radial and femoral arterial stiffness (cAIx, crPWV, cfPWV), and thigh and calf arterial compliance (Vmax50). Endothelial repair was indexed by endothelial progenitor cell colony forming units (EPC-CFU). Traditional CVD risk measures included blood pressure, central adiposity, lipids, insulin resistance (HOMA-IR), CRP and ASCVD score. Analyses controlled for demographics (age, sex, education), medications (antihypertensive, statin/fibrate, antipsychotic), and substance abuse (ASSIST).. No group differences were observed in central adiposity, HOMA-IR, CRP, or ASCVD risk score. However, the ABC- group displayed greater dyslipidemia. The ABC+ group displayed no difference on FMD, cAIx, cfPWV or calf Vmax50 compared with other groups. When CD4 count and viral load were controlled, no additional differences between the ABC+ and ABC- groups emerged. Analyses of crPWV and thigh Vmax50 suggested supported by a trend toward lower EPC-CFU in the HIV+ groups than the HIV- group.. Findings indicate that ABC treatment of 30-50 year-old PWH on stable ART is not likely to contribute in a robust way to higher CVD risk.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Vascular Diseases

Abacavir is a nucleoside reverse transcriptase inhibitor that is used as a component of the antiretroviral treatment regimen in the management of the human immunodeficiency virus for both adults and children. It is efficacious, but its use may be limited by a hypersensitivity reaction linked with the HLA-B*57:01 genotype. HLA-B*57:01 has been reported to be rare in African populations. Because of the nature of its presentation, abacavir hypersensitivity is prone to late diagnosis and treatment, especially in settings where HLA-B*57:01 genotyping is not routinely done.. We report a case of a severe hypersensitivity reaction in a 44-year-old Kenyan female living with the human immunodeficiency virus and on abacavir-containing antiretroviral therapy. The patient presented to the hospital after recurrent treatment for a throat infection with complaints of fever, headache, throat ache, vomiting, and a generalized rash. Laboratory results evidenced raised aminotransferases, for which she was advised to stop the antiretrovirals that she had recently been started on. The regimen consisted of abacavir, lamivudine, and dolutegravir. She responded well to treatment but was readmitted a day after discharge with vomiting, severe abdominal pains, diarrhea, and hypotension. Her symptoms disappeared upon admission, but she was readmitted again a few hours after discharge in a hysterical state with burning chest pain and chills. Suspecting abacavir hypersensitivity, upon interrogation she reported that she had taken the abacavir-containing antiretrovirals shortly before she was taken ill. A sample for HLA-B*57:01 was taken and tested positive. Her antiretroviral regimen was substituted to tenofovir, lamivudine, and dolutegravir, and on subsequent follow-up she has been well.. Clinicians should always be cognizant of this adverse reaction whenever they initiate an abacavir-containing therapy. We would recommend that studies be done in our setting to verify the prevalence of HLA-B*57:01.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Kenya; Lamivudine; Vomiting

Dolutegravir (DTG) plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment.. To analyze the effectiveness, durability, and safety of 2-DR compared with DTG plus abacavir/lamivudine (3-DR).. This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) patients who started 2-DR or 3-DR between July 1, 2018, and November 30, 2020. The primary end point was noninferiority, at 24 and 48 weeks, of 2-DR versus 3-DR regarding the percentage of patients with viral load (VL)≥50 and 200 copies/mL in TN (4% margin) and VL<50 and 200 copies/mL in TE (margin 12%). Durability of response, and safety were also measured.. 242 patients were included (53 TN and 189 TE). Two TN patients on 2-DR had VL≥50 copies/mL and 1 had VL≥200 copies/mL at week 24. In TE patients on 2-DR, 90.2% achieved VL<200 copies/mL at week 24 (difference: 3.8%; 95% CI = -6.3% to 14%) and 91.8% at week 48 (difference: 0.06%; 95% CI = -9% to 10%), meeting noninferiority criteria. Among the 53 TN patients, only 1 VF was observed in 2-DR. In TN patients, the risk of treatment discontinuation was similar between groups (hazard ratio [HR] = 0.37;. Our results did not show noninferiority in terms of virological effectiveness. Nevertheless, all effectiveness measures support the use of 2-DR in a real-life cohort of TN and TE. Additionally, durability and safety of 2-DR were confirmed to be similar to that of 3-DR.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Viral Load

Although individual antiretroviral drugs have been shown to be associated with elevated cardiovascular disease (CVD) risk, data are limited on the role of antiretroviral drug combinations. Therefore, we sought to investigate CVD risk associated with antiretroviral drug combinations.. Using an administrative health-plan dataset, risk of acute myocardial infarction (AMI) associated with current exposure to antiretroviral drug combinations was assessed among persons living with HIV receiving antiretroviral therapy (ART) across the U.S. from October 2009 through December 2014. To account for confounding-by-indication and for factors simultaneously acting as causal mediators and confounders, we applied inverse probability of treatment weighted marginal structural models to longitudinal data of patients.. Over 114,417 person-years (n = 73,071 persons) of ART exposure, 602 cases of AMI occurred at an event rate of 5.26 (95% CI: 4.86, 5.70)/1000 person-years. Of the 14 antiretroviral drug combinations studied, persons taking abacavir-lamivudine-darunavir had the highest incidence rate (IR: 11/1000; 95% CI: 7.4-16.0) of AMI. Risk (HR; 95% CI) of AMI was elevated for current exposure to abacavir-lamivudine-darunavir (1.91; 1.27-2.88), abacavir-lamivudine-atazanavir (1.58; 1.08-2.31), and tenofovir-emtricitabine-raltegravir (1.35; 1.07-1.71). Tenofovir-emtricitabine-efavirenz was associated with reduced risk (0.65; 0.54-0.78). Abacavir-lamivudine-darunavir was associated with increased risk of AMI beyond that expected of abacavir alone, likely attributable to darunavir co-administration. We did not find an elevated risk of AMI when abacavir-lamivudine was combined with efavirenz or raltegravir.. The antiretroviral drug combinations abacavir-lamivudine-darunavir, abacavir-lamivudine-atazanavir and tenofovir-emtricitabine-raltegravir were found to be associated with elevated risk of AMI, while tenofovir-emtricitabine-efavirenz was associated with a lower risk. The AMI risk associated with abacavir-lamivudine-darunavir was greater than what was previously described for abacavir, which could suggest an added risk from darunavir. The results should be confirmed in additional studies.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; HIV-1; Humans; Lamivudine; Myocardial Infarction; Tenofovir; United States

The efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC + RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed individuals. This study evaluated the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy in virologically suppressed HIV-1 infected individuals in Singapore.. In this retrospective, single-centre study, we included individuals who were prescribed ABC/3TC + RPV, had HIV-1 viral load (VL) < 50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. The follow-up period was 48 ± 12 weeks. The primary outcome was the proportion of individuals who maintained virologic suppression of HIV-1 VL < 50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance profiles associated with virologic failure, changes in immunologic and metabolic parameters, and the safety profile of ABC/3TC + RPV.. A total of 222 individuals were included in the study. The primary outcome was achieved in 197 individuals [88.8%, 95% confidence interval: 83.7-92.4%]. There were 21 individuals (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 individuals experienced virologic failure, of whom, 3 of these individuals had developed emergent antiretroviral resistance and had HIV-1 VL > 500 copies/ml at the end of the 48 ± 12 weeks follow-up period. The remaining individual experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 individuals (14.0%), which led to 13 individuals discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (53.1%). A statistically significant increase in CD4 was observed (p < 0.01), with a median absolute change of 31 cells/uL (interquartile range: - 31.50 to 140.75). No significant changes in lipid profiles were detected.. ABC/3TC + RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 individuals with in Singapore.

Topics: Anti-HIV Agents; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Lamivudine; Retrospective Studies; Rilpivirine; Singapore

Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.

Topics: Anti-HIV Agents; Child; Dideoxynucleosides; HIV; HIV Infections; Humans; Infant; Infant, Newborn

Abacavir (ABC) is an HIV nucleotide-analogue reverse transcriptase inhibitor that can produce a severe hypersensitivity reaction (ABC-HSR) in about 5% of the patients. The HLA-B*57:01 allele is associated with the development of ABC-HSR. Therefore, HLA-B*57:01 genotyping is required prior to the prescription of ABC. The technique routinely used in our laboratory is the sequence-specific oligonucleotide probes (SSOP) reverse hybridization method followed by Sanger sequencing. This technique is time-consuming and expensive. The single-nucleotide polymorphism (SNP) HCP5 rs2395029 was described to be in complete linkage disequilibrium with HLA-B*57:01. In this study, we aimed to assess the linkage disequilibrium between HCP5 rs2395029 and HLA-B*57:01 in patients receiving medical assistance at our hospital. We selected 226 HIV-infected patients from our hospital who had been routinely genotyped since 2009 with the SSOP and Sanger sequencing method: 49 HLA-B*57:01 positives and 177 negatives. We genotyped them for HCP5 rs2395019 by real time PCR (qPCR). We exploratory performed two copy number variation assays flanking HCP5 rs2395019 to explore possible deletions that could break the linkage disequilibrium with HLA-B*57:01. The concordance between HLA-B*57:01 and the HCP5 rs2395029 G allele was absolute, with a specificity and sensitivity of 100% (95% confidence interval: 93.0-100.0% and 98.0-100.0%, respectively) and estimated positive and negative predictive values of 84.4% (48.1-93.9%) and 99.9% (99.4-100.0%), respectively. No deletions were found at HCP5 flanking regions. The duration and cost of the SSOP-based method was considerably higher than the SNP-based method. Therefore, the HCP5 rs2395029 genotyping method may be alternatively used in the clinical practice.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; DNA Copy Number Variations; Drug Hypersensitivity; Genotype; HIV Infections; HLA-B Antigens; Humans; Linkage Disequilibrium; Polymorphism, Single Nucleotide; RNA, Long Noncoding

Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era.. Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time.. Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens.. There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.

Topics: Adult; Alanine; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Weight Gain

Topics: Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin; Lamivudine; Menopause; Nitriles; Oxazines; Piperazines; Pyridones; Pyrimidines; Raltegravir Potassium; Waist Circumference; Weight Gain

D-dimer concentrations in people living with HIV (PLHIV) on combination antiretroviral therapy (cART) are increased and have been linked to mortality. D-dimer is a biomarker of in vivo coagulation. In contrast to reports on D-dimer, data on coagulation capacity in PLHIV are conflicting. In this study, we assessed the effect of cART and inflammation on coagulation capacity.. We explored coagulation capacity using calibrated thrombin generation (TG) and linked this to persistent inflammation and cART in a cross-sectional study including PLHIV with viral suppression and uninfected controls.. We used multivariate analyses to identify independent factors influencing in vivo coagulation (D-dimer) and ex vivo coagulation capacity (TG).. Among 208 PLHIV, 94 (45%) were on an abacavir-containing regimen. D-dimer levels (219.1 vs 170.5 ng/mL, P = 0.001) and inflammatory makers (sCD14, sCD163, and high-sensitive C-reactive protein) were increased in PLHIV compared with those in controls (n = 56). PLHIV experienced lower TG (reflected by endogenous thrombin potential [ETP]) when compared with controls, after correction for age, sex, and antiretroviral therapy. Abacavir use was independently associated with increased ETP. Prothrombin concentrations were strongly associated with ETP and lower in PLHIV on a non-abacavir-containing regimen compared with those in controls, suggesting consumption as a possible mechanism for HIV-associated reduction in TG. D-dimer concentrations were associated with inflammation, but not TG.. Abacavir use was associated with increased TG and could serve as an additional factor in the reported increase in thrombotic events during abacavir use. Increased exposure to triggers that propagate coagulation, such as inflammation, likely underlie increased D-dimer concentrations found in most PLHIV.

Topics: Adult; Anti-HIV Agents; Biomarkers; Blood Coagulation; C-Reactive Protein; Cross-Sectional Studies; Dideoxynucleosides; Female; Fibrin Fibrinogen Degradation Products; HIV Infections; Humans; Inflammation; Lipopolysaccharide Receptors; Male; Middle Aged; Plasma; Prospective Studies; Thrombomodulin

The presence of the human leukocyte antigen HLA-B*57:01 is associated with the development of a hypersensitivity reaction to abacavir (ABC). Limited data exist on HLA-B*57:01 prevalence in individuals with HIV-1 in Africa. This study aimed to estimate HLA-B*57:01 prevalence in individuals with HIV-1 in West and Central Africa.. A cross-sectional study was conducted in four countries in West and central Africa (Burkina-Faso, Côte d'Ivoire, Gabon, and Togo) from January 2016 to February 2020 to determine the status of HLA-B*57:01 in adults with HIV-1. The presence of HLA-B*57:01 was determined by using Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) in blood samples. Prevalence rates were stratified based on country.. A total of 4016 (69.8% women) individuals with HIV were enrolled. Their median age was 45, and the interquartile range was 38-52. We included 500 (12.4%) patients in Burkina-Faso, 1453 (36.2%) in Côte d'Ivoire, 951 (23.7%) in Gabon, and 1112 (27.7%) in Togo. The overall HLA-B*57:01 prevalence was 0.1% [95% CI: 0.0-0.2%]. The prevalence of HLA-B*57:01 was similar according to the four countries. Only one case was reported in each country except Togo, with no cases.. HLA-B*57:01 prevalence is low in individuals with HIV in West and central Africa, and there is no difference among countries. This study does not confirm the utility of HLA-B*57:01 allele testing for abacavir use in this region.

Topics: Adult; Africa, Central; Africa, Western; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Middle Aged; Prevalence

Combination antiretroviral therapy is the mainstay of HIV treatment, lowering plasma viral levels below detection. However, eradication of HIV is a major challenge due to cellular and anatomical viral reservoirs that are often protected from treatment by efflux transporters, such as P-glycoprotein (P-gp) at the blood-brain barrier (BBB). Herein we described a Trojan horse approach to therapeutic evasion of P-gp based on a reversibly linked combination of HIV reverse transcriptase and protease inhibitors. Potent inhibition of P-gp efflux in cells, including human brain endothelial cells, was observed with the linked heterodimeric compounds. In vitro regeneration of active monomeric drugs was observed in a reducing environment with these dimeric prodrugs, with the superior leaving group promoting more facile release from the tether. These release trends were mirrored in the efficacy of the in cyto anti-HIV-1 activity of the Trojan horse heterodimers.

Topics: Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Brain; Cell Line; Dimerization; Drug Development; HIV Infections; HIV-1; Humans; Models, Molecular; Prodrugs

The time at which the protective effect of starting ART is achieved in male rectal and genital reservoirs is not clearly established.. To quantify HIV-1 RNA decay towards virological suppression in rectal mucosa and semen in MSM starting dolutegravir/abacavir/lamivudine (DTG/ABC/3TC).. A longitudinal cohort study of ART-naive HIV-positive MSM was performed. HIV-1 RNA was quantified in rectal mucosa and seminal plasma samples at day 1 of ART initiation (baseline) and every 4 weeks until week 20 (w20; all participants) and week 64 (w64; 6 of 12 participants).. Twelve MSM, with median (IQR) age 36 (33-40) years and baseline CD4+ count 449 (411-503) cells/mm3, were included. At baseline, HIV-1 RNA was detectable in all plasma and seminal samples and 10/12 rectal samples. All participants achieved plasma virological suppression by w20, whereas HIV-1 RNA was detectable in 42% and 50% of seminal and rectal samples, respectively. At w64, HIV-1 RNA was detectable in 1/6 seminal and 1/6 rectal samples. A relationship of baseline seminal and rectal HIV-1 RNA levels with viral shedding in reservoirs (HIV-1 RNA >200 copies/mL or copies/swab) was found. In addition, a significant association of baseline plasma viral load with time to rectal HIV-1 RNA <200 copies/swab was found (P=0.025).. Viral decay after initiating DTG/ABC/3TC is slower in rectal mucosa and semen than in plasma. Approximately half of patients achieved undetectable HIV-1 RNA levels in rectal and genital secretions at w20 and in some patients viral shedding persisted for up to 1 year. Initial plasma viral load influences time to rectal suppression.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Homosexuality, Male; Humans; Lamivudine; Longitudinal Studies; Male; Oxazines; Piperazines; Pyridones; RNA Stability; RNA, Viral; Sexual and Gender Minorities; Viral Load

Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.

Topics: Adult; Anti-Retroviral Agents; Bariatric Surgery; Dideoxynucleosides; Drug Monitoring; Gastrectomy; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Obesity, Morbid; Oxazines; Piperazines; Pyridones

Topics: Adult; Alanine; Anti-HIV Agents; Deglutition Disorders; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Eosinophilic Esophagitis; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load

M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I.. We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors.. A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50 copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12 months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia.. During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL <50 copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up.. M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months.

Topics: Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Retrospective Studies; Viral Load

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Topics: Anti-HIV Agents; Antitubercular Agents; Biological Availability; Child; Child, Preschool; Dideoxynucleosides; Drug Combinations; Drug Interactions; HIV Infections; Humans; Lopinavir; Prospective Studies; Rifampin; Ritonavir; Tuberculosis, Pulmonary

Abacavir (ABC) and Zidovudine (AZT) based regimens are the preferred first line nucleoside reverse transcriptase (NRTIs) backbones being widely utilized for managing HIV infection in children. However, there is a dearth of data regarding the clinical outcomes and associated risk factors in Ethiopia. We compared the proportion of mortality and the rate of occurrence of Opportunistic Infections (OIs) with ABC versus AZT -based regimens in a cohort of HIV-infected children.. A 42 months retrospective cohort study was conducted. A total of 179 records were reviewed by including data from October 2014 to April 2017. Data were collected on socio-demographic, clinical characteristics of patients and drug related variables. Data were analyzed using STATA13.1. Kaplan-Meier and Cox regression were used to compare survival experience and identify independent predictors. Propensity score matching analysis was conducted to elucidate the average treatment effects of each regimen over OIs.. Of 179 patients, 98 (54.7%) were females. The mean (+SD) age of the study subjects was 6.53 ± 2.83 years. Through 42 months analysis, a total of 4 patients (1 (1.14%) from ABC group and 3 (3.3%) from AZT group (p = 0.339)) were died. The incidence of opportunistic infections attributed to ABC group was 8.77/100,000 person years (py) and that of AZT was 6.9/100,000py. The incidence rate ratio (IRR) for OIs was (IRR = 0.87, 95% CI [0.49-1.53] (p = 0.304). Baseline CD4 count (AHR = 0.99, 95% CI [0.98-0.99]), Severe acute malnutrition (AHR = 15.92, 95% CI [5.34-47.50]), and exposure to tuberculosis treatment (AHR = 2.93, 95% CI [1.39-6.17]) were the independent predictors for the development of OIs.. ABC and AZT based ART regimens seem to have comparable survival benefit among HIV-infected children in Ethiopia. Therefore, both regimens might be used as an alternative in resource limited settings.

Topics: Anti-HIV Agents; Child; Child, Preschool; Cohort Studies; Developing Countries; Dideoxynucleosides; Ethiopia; Female; HIV Infections; Humans; Male; Retrospective Studies; Zidovudine

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

Topics: Allergens; Aminopeptidases; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity Syndrome; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Lipopolysaccharide Receptors; Male; Minor Histocompatibility Antigens; Phenotype; Retrospective Studies

Carriage of human leukocyte antigen (HLA)-B*57:01 allele increases the risk of abacavir hypersensitivity reaction. Therefore, since 2008 HIV treatment guidelines recommend HLA-B*57:01 screening before abacavir administration, greatly reducing hypersensitivity reaction rate. However, clinically suspected abacavir-related hypersensitivity reactions are described in allele non-carriers. Major aim of this study was to evaluate the relationship between HLA-B*57:01 pattern and abacavir-related hypersensitivity reaction, focusing on hypersensitivity reaction prevalence in allele non-carriers.. We included all outpatients aged >18 years old with HIV infection and known HLA-B*57:01 pattern, followed at our Department from January 2000 until December 2017. Patients were divided according to HLA-B*57:01 pattern and first antiretroviral treatment prescribed (containing or not abacavir) as follows: HLA-B*57:01 allele carriers treated with abacavir and HLA-B*57:01 allele non-carriers treated with abacavir. We considered all adverse events reported during first abacavir administration, differentiating between confirmed hypersensitivity reactions and non-hypersensitivity reactions, according to abacavir hypersensitivity reaction definition included in the abacavir EU Summary of Product Characteristics and the US Prescribing Information.. A total of 3144 patients had a known HLA-B*57:01 pattern. About 5.4% of them showed allele polymorphism; Caucasian ethnicity was the most represented. In this cohort, 1801 patients were treated with a first abacavir-containing regimen (98.2% of them was represented by allele non-carriers). 191 out of 1801 patients discontinued abacavir because of toxicity/intolerance; among them 107 described adverse events fulfilled the criteria of confirmed abacavir hypersensitivity reaction (22/32 allele-positive patients and 85/1769 allele-negative patients). After having experienced a confirmed abacavir hypersensitivity reaction, abacavir was re-administered to eight HLA-B*57:01 negative patients. Seven of them re-experienced a syndrome consistent with hypersensitivity reaction, finally leading to drug discontinuation. Overall, no fatal reactions were described.. Not all abacavir-related side effects occur as a result of classic HLA-B*57:01-mediated hypersensitivity reaction, as they can develop irrespective of HLA-B*57:01 status. Clinical vigilance must be an essential part of the management of individuals starting abacavir, at any time during treatment. In a 'real-life' setting, clinical diagnosis of suspected abacavir hypersensitivity reaction in allele non-carriers remains crucial for further clinical decision making.

Topics: Adult; Anti-HIV Agents; Clinical Decision-Making; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; Haplotypes; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Oxazines; Pandemics; Piperazines; Pneumonia, Viral; Pyridones; Ritonavir; SARS-CoV-2; Tenofovir; Transgender Persons

Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear.. To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment.. An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods.. Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04).. After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed.

Topics: Anti-HIV Agents; Bone Density; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Prospective Studies; Pyridones

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Emtricitabine; Fractures, Bone; HIV Infections; Humans; Incidence; Lamivudine; Osteoporotic Fractures; Tenofovir

A 26-year-old male living with human immunodeficiency virus (HIV) and who had previously been treated for ocular syphilis presented to the Emergency Department with progressive vision loss and uveitis. The efficacy of standard management for neurosyphilis in HIV and recurrence was examined.

Topics: Adult; AIDS-Related Opportunistic Infections; Dideoxynucleosides; Eye Infections, Bacterial; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Neurosyphilis; Oxazines; Penicillin G; Piperazines; Pyridones; Syphilis; Syphilis Serodiagnosis; Treatment Outcome; Treponema pallidum; Uveitis; Visual Acuity

Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

Topics: Anti-HIV Agents; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; Antiretroviral Therapy, Highly Active; Child, Preschool; Cohort Studies; Dideoxynucleosides; Drug Combinations; HIV Antibodies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Lopinavir; Ritonavir; Viral Load; Zidovudine

Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.

Topics: Alleles; Antibodies, Immobilized; Antibodies, Monoclonal; Biosensing Techniques; Dideoxynucleosides; Drug Hypersensitivity; Electrochemical Techniques; Electrodes; HIV Infections; HLA-B Antigens; Humans; Leukocytes, Mononuclear

Adolescents with perinatally acquired HIV (PHIV) are at risk of chronic disease due to long-standing immune suppression, HIV disease and antiretroviral therapy (ART) exposure. However, there are few data on multisystem disease in this population. We investigated the overlapping burden of neurocognitive, cardiovascular, respiratory and/or renal impairment among PHIV positive (PHIV+) adolescents.. In this cross-sectional analysis, participants aged 9 to 14 years on ART for >6 months were recruited from seven sites across Cape Town from July 2013 through March 2015, together with age-matched HIV-negative (HIV-) adolescents. Impairment at enrolment was assessed across neurocognitive functioning (using the youth-International HIV Dementia Scale); cardiac function (echocardiogram abnormality); respiratory function (abnormal spirometry) and renal function (abnormal glomerular filtration rate).. Overall, 384 PHIV+ and 95 HIV- adolescents were included (mean age, 11.9 years; 49% female). Median age of ART initiation was 4.2 years (IQR: 1.7 to 7.6) and median CD4 count was 709 (IQR: 556 to 944) with 302 (79%) of PHIV+ adolescents virologically suppressed. Abacavir and Zidovudine were the most commonly used nucleoside reverse transcriptase inhibitors (NRTIs) with 60% of adolescents on non-nucleoside reverse transcriptase inhibitors (NNRTI) and 38% on a protease inhibitor (PI). Among PHIV+ adolescents, 167 (43.5%) had single system impairment only, 110 (28.6%) had two systems involved, and 39 (10.2%) had three or four systems involved. PHIV+ participants had more 2-system and 3-system impairment than HIV-, 110 (28.6%) versus 17 (17.9%), p = 0.03 and 39 (10.2%) versus 3 (4.3%), p = 0.03. PHIV+ participants who had failed a year of school (73.8% vs. 46.4%, p = 0.00) and with a viral load >1000 copies/mL at enrolment (16.8% vs. 8.1%, p = 0.03) were more likely to have dual or multisystem impairment. Of those with cardiac impairment, 86.7% had an additional system impaired. Similarly, in those with neurocognitive impairment, almost 60% had additional systems impaired and of those with respiratory impairment, 74% had additional systems impaired.. Despite relatively early ART initiation, there is a substantial burden of multisystem chronic impairment among PHIV+ adolescents. This phenomenon needs to be further explored as this population ages and begins to engage in adult lifestyle factors that may compound these impairments.

Topics: Adolescent; Anti-Retroviral Agents; Cardiovascular Diseases; CD4 Lymphocyte Count; Child; Cognition Disorders; Cross-Sectional Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Kidney Diseases; Male; Respiratory Tract Diseases; South Africa; Viral Load; Zidovudine

We studied 48 children receiving abacavir-based HAART regimen, over a period of one-year for side effects and failure rates. None of the children developed hypersensitivity reaction. The CD4 count significantly improved from the time of enrolment till 12 months of therapy while the failure rate was 14.5%.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Male; Treatment Outcome

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Illinois; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Prisoners; Prisons; Pyridones; Retrospective Studies; Treatment Outcome

Combined antiretroviral therapy (cART) consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz, is still the first-line treatment in resource-limited settings. However, efavirenz has shown strong prominence of disadvantages with variance in plasma concentration and central nervous side effects. Our study presents HIV infected, drug naïve, female patient with relatively low BMI,

Topics: Adult; Alkynes; Benzoxazines; Body Mass Index; Chemical and Drug Induced Liver Injury; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors

Alternative modes of antiretroviral administration are sought for people with impaired intestinal passage and/or absorption. We present a case of late HIV diagnosis (CD4+ count 160 cells/µL) with gastric outlet obstruction due to stomach adenocarcinoma. Co-morbidities included oesophageal candidiasis, Helicobacter pylori-positive duodenal ulcers and cytomegalovirus duodenitis. The gastric outlet obstruction required total parenteral nutrition and parenteral medication during four weeks of diagnostic work-up leading to pyloric resection. Crushed dolutegravir, abacavir and lamivudine were administered during this time in the evening via nasogastric tube, which was kept clamped overnight. The tube was unclamped in the morning and stomach content was drained during the daytime. This mode of administration resulted in rapid and sustained viral load suppression (from 300,000 to 115 copies per mL in 28 days, 81 copies/mL after 42 days of treatment and less than 40 copies/mL thereafter). Therapeutic drug monitoring confirmed sufficient antiretroviral plasma levels during this mode of administration. The absorption of crushed dolutegravir, abacavir and lamivudine in the stomach may be considered in people with questionable gastrointestinal passage or impaired gastric emptying to achieve viral load suppression.

Topics: Adenocarcinoma; Anti-Retroviral Agents; Dideoxynucleosides; Gastric Outlet Obstruction; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Intubation, Gastrointestinal; Lamivudine; Male; Middle Aged; Oxazines; Parenteral Nutrition; Piperazines; Pyridones; Stomach Neoplasms; Sustained Virologic Response; Treatment Outcome

Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients.. ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs.. In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype.. This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism.

Topics: Adult; Aged; Diabetes Mellitus; Didanosine; Dideoxynucleosides; Erythrocytes; Female; Genotype; HIV Infections; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Pyrophosphatases; Reverse Transcriptase Inhibitors; Tenofovir

No single-tablet antiretroviral (ARV) regimens (STRs) are approved for patients with human immunodeficiency virus (HIV) and end-stage renal disease (ESRD) on hemodialysis (HD). Based on known pharmacokinetic (PK) properties, abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTG) STR may represent a promising option. This case series presents the safety and efficacy of ABC/3TC/DTG STR in patients with HIV and ESRD on HD. Patients were included if they were HIV-positive, maintained on intermittent HD for ESRD, switched to an ARV regimen containing ABC/3TC/DTG, and had at least one set of virologic data before and after the switch. Average age (±standard deviation) was 59 (±8) years. The majority of patients were cis-gender male and non-Hispanic Black. Only one demonstrated clinically significant resistance at baseline. All were on multiple-tablet regimens prior to the switch. Five patients (83%) achieved undetectable HIV-RNA after the switch while only four patients (46%) were undetectable immediately prior. No decline in immune function was noted. ABC/3TC/DTG STR was well tolerated. Only one patient self-reported an adverse event (nausea), which resolved without drug discontinuation. Based on these data, it appears that ABC/3TC/DTG may be a safe and effective ARV-STR option for patients with HIV and ESRD on HD. A larger trial including a PK analysis is needed to confirm these findings.

Topics: Adult; Aged; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Dideoxynucleosides; Drug Combinations; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Kidney Failure, Chronic; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Renal Dialysis; Tablets; Treatment Outcome; Viral Load

Topics: Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

HLA-B*57:01 screening was added to clinical care guidelines in 2008 to reduce the risk of hypersensitivity reaction from abacavir. The uptake of HLA-B*57:01 screening and incidence of hypersensitivity reaction were assessed in a prospective clinical cohort in the United States to evaluate the effectiveness of this intervention.. We included all patients initiating an abacavir-containing regimen for the first time in the pre-HLA-B*57:01 screening period (January 1, 1999 to June 14, 2008) or the post-HLA-B*57:01 screening period (June 15, 2008 to January 1, 2016). Yearly incidence of both HLA-B*57:01 screening and physician panel-adjudicated hypersensitivity reactions were calculated and compared.. Of the 9619 patients eligible for the study, 33% initiated abacavir in the pre-screening period and 67% in the post-screening period. Incidence of HLA-B*57:01 screening prior to abacavir initiation increased from 43% in 2009 to 84% in 2015. The incidence of definite or probable hypersensitivity reactions decreased from 1.3% in the pre-screening period to 0.8% in 2009 and further to 0.2% in 2015 in the post-screening period.. Frequency of HLA-B*57:01 screening increased steadily since its first inclusion in treatment guidelines in the United States. This increase in screening was accompanied by a decreasing incidence of definite or probable hypersensitivity reactions over the same period. However, a considerable proportion of patients initiating abacavir were not screened, representing a failed opportunity to prevent hypersensitivity reactions. Where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Electronic Health Records; Female; HIV Infections; HLA-B Antigens; Humans; Male; Mass Screening; Middle Aged; Practice Guidelines as Topic; Prospective Studies

Concerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals.. We performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan-Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.. About 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC-based triple-therapies, aHR = 3.56, p = 0.012 for tenofovir-based) and for toxicity (aHR = 5.26, p = 0.030 for ABC-based, aHR = 6.60, p = 0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.. In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Italy; Male; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Retrospective Studies; Tenofovir; Treatment Outcome

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Kidney Function Tests; Lamivudine; Liver Function Tests; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Triglycerides

Topics: Adenine; Alanine; Amides; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tenofovir

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood-brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat- mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.

Topics: Animals; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Capillary Permeability; Corpus Striatum; Dextrans; Dideoxynucleosides; Female; Fluorescein-5-isothiocyanate; Heterocyclic Compounds, 3-Ring; Hippocampus; HIV Infections; HIV-1; Lamivudine; Mice; Mice, Transgenic; Models, Biological; Morphine; Neurocognitive Disorders; Oxazines; Piperazines; Pyridones; tat Gene Products, Human Immunodeficiency Virus

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Immunologic Memory

Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ individuals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-γ production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed.

Topics: Alleles; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; gag Gene Products, Human Immunodeficiency Virus; Histocompatibility Testing; HIV Infections; HIV Seropositivity; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Receptors, Antigen, T-Cell; T-Lymphocytes; Tumor Necrosis Factor Receptor Superfamily, Member 9

Topics: Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Testing; Genotype; Genotyping Techniques; HIV Infections; HLA-B Antigens; Humans; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Risk Assessment; Singapore

Trends in resistance to antiretroviral drugs for HIV-1 may inform clinical support and drug development. We evaluated drug resistance mutation (DRM) trends for nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), and integrase strand transfer inhibitor (INSTI) in a large U.S. reference laboratory database. DRMs with a Stanford HIV Drug Resistance Database mutation score ≥10 from deidentified subtype B NRTI/NNRTI/PI specimens (2006-2017; >10,000/year) and INSTI specimens (2010-2017; >1,000/year) were evaluated. Sequences with NRTI, NNRTI, or PI single- or multiclass DRMs declined from 48.9% to 39.3%. High-level dual- and triple-class resistance declined from 43.3% (2006) to 17.1% (2017), while sequences with only single-class DRMs increased from 40.0% to 52.9%. The prevalence of DRMs associated with earlier treatment regimens declined, while prevalence of some DRMs associated with newer regimens increased. M184V/I decreased from 48.3% to 29.4%. K103N/S/T declined from 42.5% in 2012 to 36.4% in 2017. Rilpivirine and etravirine DRMs E138A/Q/R and E138K increased from 4.9% and 0.4% to 9.7% and 1.7%, respectively. Sequences with ≥1 darunavir DRM declined from 18.1% to 4.8% by 2017. INSTI DRM Q148H/K/R declined from 39.3% (2010) to 13.8% (2017). Prevalence of elvitegravir-associated DRMs T66A/I/K, E92Q, S147G, and the dolutegravir-associated DRM R263K increased. For a subset of patients with serial testing, 50% (2,646/5,290) of those who initially had no reportable DRM subsequently developed ≥1 DRM for NRTI/NNRTI/PI and 49.7% (159/320) for INSTI. These trends may inform the need for baseline genotypic resistance testing. The detection of treatment-emergent DRMs in serially tested patients confirms the value of genotypic testing following virologic failure.

Topics: Anti-HIV Agents; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Mutation; Nitriles; Oxazines; Piperazines; Pyridazines; Pyridones; Pyrimidines; Reverse Transcriptase Inhibitors; Rilpivirine

Dolutegravir (DTG) is recommended as part of first-line antiretroviral therapy (ART) for people living with HIV(PLHIV). We sought to determine the rate of adverse events (AEs) and discontinuations among Thais treated during acute HIV infection (AHI) and switched to DTG-based regimens.. Thai participants in the SEARCH010/RV254 cohort who initiated ART during AHI and switched to DTG for at least 48 weeks were prospectively observed and included in the analysis. Rates and characteristics of DTG-related AEs and discontinuations were described.. A total of 313 Thai participants were included in the analysis. The median age was 29 years, 96% were male, 64% had a Bachelor's degree or higher and 16% had a body mass index (BMI) <18.5 kg/m. DTG was well tolerated with few discontinuations in this cohort of young men. Incident hepatitis C virus infection was a driver of liver-related AEs leading to discontinuations. In populations at risk, regular testing for hepatitis C virus during ART is recommended to anticipate possible AEs, guide management and improve safety.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Female; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Risk Factors; Thailand; Young Adult

To investigate the association between abacavir (ABC) use and recurrent myocardial infarction (MI) among HIV-positive people with a prior MI.. International multicohort collaboration with follow-up from 1999 to 2016.. The rate of recurrent MI was described among D:A:D participants who experienced an index MI whilst in the study, and who remained under follow-up beyond 28 days after this MI. Follow-up was considered to the date of next MI, death, 1 February 2016 or 6 months after last clinic visit. Poisson regression models considered associations between recurrent MI and exposure to ABC (use at index MI, current post-MI exposure and cumulative exposure), before and after adjusting for calendar year.. The 984 individuals who experienced an index MI during the study (91.3% male, median age 51 at index MI) were followed for 5312 person-years, over which time there were 136 recurrent MIs (rate 2.56/100 person-years, 95% confidence interval 2.13-2.99). Rates were 2.40 (1.71-3.09) and 2.65 (2.10-3.21)/100 person-years in those who were and were not on ABC, respectively, at the index MI, and 2.90 (2.01-3.78) and 2.44 (1.95-2.93)/100 person-years in those who were and were not currently receiving ABC, respectively, post-MI. No association was seen with recurrent MI and either cumulative exposure to ABC [relative rate 0.86 (0.68-1.10)/5 years], receipt of ABC at index MI [0.90 (0.63-1.29)] nor recent post-MI exposure to ABC [1.19 (0.82-1.71)].. Among people with a previous MI, there was no evidence for an association between use of ABC post-MI and an elevated risk of a recurrent MI.

Topics: Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Recurrence; Risk Assessment

To determine the prevalence of HLA-B*5701 allele in HIV-infected children, and to find its association with Abacavir hypersensitivity.. Children (2 to 18 y) already on, or to be initiated on Abacavir were included for PCR sequencing to detect HLA-B*5701.. proportion with HLA B*5701 allele and hypersensitivity with Abacavir. Abacavir was stopped if patient tested positive for HLA-B*5701 allele.. 100 children (median age 11 y) were enrolled; 10 were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%) children. Two of these 11 children developed hypersensitivity after initiation of Abacavir. Abacavir was thereafter stopped in all who tested HLA-B*5701 positive, irrespective of the development of hypersensitivity reaction.. HLA-B*5701 allele was present in 11 (11%) of HIV-infected children, of which two developed Abacavir hypersensitivity. None of the patients without the allele developed hypersensitivity.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; India; Male; Prospective Studies

Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC.. We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation.. Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity.. ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Drug Utilization; Europe; Female; HIV Infections; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Poisson Distribution

There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV.. Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence.. Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome.. Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Topics: Adult; Aged; Antirheumatic Agents; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; North America; Risk Assessment; Risk Factors

Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml

Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Dideoxynucleosides; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Tandem Mass Spectrometry; Time Factors; Treatment Outcome

A regimen with rilpivirine (RPV), abacavir (ABC) and lamivudine (3TC) is simple and may allow the sparing of tenofovir and protease inhibitors. However, data on use of this combination as a strategy of switch are limited. Aims of the study were to assess the long-term efficacy and safety of this regimen.. Retrospective study on HIV-1 infected patients followed at the Infectious Disease Department of the San Raffaele Scientific Institute, HBsAg-negative, HLA B5701-negative, with no documented resistance to RPV, ABC and 3TC, with HIV-RNA<50 copies/mL who started RPV plus ABC/3TC from March 2013 to September 2015. The primary outcome was durability [no treatment failure (TF)]. Secondary objectives were to evaluate changes in immunological, metabolic and other safety parameters. TF was defined as the occurrence of virological failure (VF, 2 consecutive values >50 copies/mL) or discontinuation of any drug in the regimen for any reason. Patients' follow-up accrued from the date of RPV plus ABC/3TC initiation to the date of TF (VF or discontinuation of any drug in the regimen) or to the date of last available visit. Time to TF was evaluated by use of the Kaplan-Meier curves. Mixed linear models were applied to evaluate changes in immunological, metabolic and other safety parameters.. In this analysis, 100 patients starting RPV plus ABC/3TC were included. By 12, 24 and 36 months after switching to RPV plus ABC/3TC, the proportions of individuals without TF were 88% [95% confidence interval (CI): 79%-93%], 82% (95% CI:73%-89%) and 78% (95% CI:68%-86%), respectively. Time to TF was not significantly influenced by CD4+ nadir (≤200 vs >200 cells/μl; log-rank test: p = 0.311) or pre-ART viral load (<100000 vs ≥100000 copies/mL; log-rank test: p = 0.574) or the type of previous antiretroviral regimen (PI+2NRTIs vs NNRTI+2NRTIs vs Other; log-rank test: p = 0.942). Over a median follow-up of 2.9 years (IQR: 1.9-3.5), 26 subjects discontinued the treatment [10 due to toxicity, 7 for interactions with other drugs, 3 due to cardiovascular risk concern, 2 due to single viral blip, 1 due to VF, 1 for asthma, 1 patient's decision, 1 due to enrolment in a study protocol].. In this retrospective study, long-term use of RPV plus ABC/3TC regimen is effective and safe. Efficacy of this regimen was not found to be affected by low CD4+ nadir or high pre-ART viral load.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Kaplan-Meier Estimate; Lamivudine; Linear Models; Male; Middle Aged; Retrospective Studies; Rilpivirine; Time Factors; Treatment Failure; Viral Load

In April 2010, tenofovir and abacavir replaced stavudine in public sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for paediatric patients 3-19 years of age at eight public sector clinics in Johannesburg, South Africa.. Cohort analysis of treatment-naïve, non-pregnant paediatric patients from 3 to 19 years old initiated on ART between April 2004 and December 2013. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir and/or abacavir was substituted for stavudine after April 2010 in first-line ART. We evaluated the frequency and type of single-drug substitutions, treatment interruptions and switches to second-line therapy. Fine and Gray competing risk regression models were used to evaluate the association of antiretroviral drug type with single-drug substitutions, treatment interruptions and second-line switches in the first 24 months on treatment.. Three hundred and ninety-eight (15.3%) single-drug substitutions, 187 (7.2%) treatment interruptions and 86 (3.3%) switches to second-line therapy occurred among 2602 paediatric patients over 24-months on ART. Overall, the rate of single-drug substitutions started to increase in 2009, peaked in 2011 at 25% and then declined to 10% in 2013, well after the integration of tenofovir into paediatric regimens; no patients over the age of 3 were initiated on abacavir for first-line therapy. Competing risk regression models showed patients on zidovudine or stavudine had upwards of a fivefold increase in single-drug substitution vs. patients initiated on tenofovir in the first 24 months on ART. Older adolescents also had a two- to threefold increase in treatment interruptions and switches to second-line therapy compared to younger patients in the first 24 months on ART.. The decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.

Topics: Adolescent; Anti-Retroviral Agents; Child; Child, Preschool; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Public Sector; South Africa; Tenofovir; Time Factors; Treatment Outcome; Young Adult

Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.. A prospective cohort of human immunodeficiency virus (HIV)-infected participants with suppressed virological replication was recruited to compare whole-blood telomere length (measured by quantitative multiplex polymerase chain reaction analysis) in participants with current exposure to tenofovir disoproxil fumarate (TDF) to that in participants never exposed to TDF.. A total of 172 participants were included: 67 were in the TDF group, and 105 were in the non-TDF group (75 were receiving 2 nucleosides [of whom 69 were receiving abacavir], 25 were receiving a nucleos[t]ide reverse transcriptase inhibitor [N{t}RTI]-sparing regimen, and 5 were receiving lamivudine as the only nucleoside). After 2 years, the mean blood telomere length increased significantly in the whole cohort. The TDF group had significantly smaller gains in telomere length than the non-TDF group. In the analysis restricted to participants receiving N(t)RTIs, TDF exposure was not associated with an independent negative effect. In the non-TDF group, participants treated with 2 nucleosides also had significantly smaller gains in telomere length than those receiving N(t)RTI-sparing regimens or lamivudine as the only nucleoside.. In HIV-infected adults with prolonged virological suppression, treatment with TDF or abacavir was associated with smaller gains in blood telomere length after 2 years of follow-up.

Topics: Adult; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Telomerase; Telomere; Tenofovir; Viral Load

Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Interactions; HIV Infections; Humans; Male; Middle Aged; Nevirapine

Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study was to evaluate trends of biochemical and inflammatory indices in patients switching to dual therapy (DT).. We included patients that a) switched to a DT from 2007 to 2015 from a tenofovir/abacavir-based triple regimen b) previously maintained a triple and c) subsequently a dual regimen for 12 months with virological suppression. We retrieved data measured at 5 points (at the switch, 6 and 12 months before and after switch). We used platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and CD4/CD8 ratio as inflammatory indices. We assessed temporal trends of viro-immunological, biochemical and inflammatory parameters.. Overall, 364 and 65 patients switched from a tenofovir- and an abacavir-triple regimen, respectively. In the tenofovir-reducing group, creatinine clearance and lipids raised after the switch. There was a significant increase in both CD4+ cells and CD4/CD8. CD8+ cells rose after the switch, while opposite trend was found for PLR. In the abacavir-reducing group total lipids showed a decrease during the first 6 months after the switch and then stabilized. An increase of CD4+ and a decrease of CD8+ cells was observed during the study period, although not statistically significant. While CD4/CD8 remained stable after simplification, PLR decreased significantly after 6 months, then returning to baseline. CD8+ cells increased in the tenofovir-reducing group despite a viro-immunological response. Intriguingly, PLR decreased, maintaining this trend for 12 and 6 months after tenofovir and abacavir interruption respectively.. Increased PLR has been linked to hypercholesterolemia and metabolic-syndrome, while high CD8+ cells count to increased risk of non-AIDS-related events regardless of CD4 T-cell recovery and to virological failure. Whether these findings may have clinical implications, and which role DT plays on the immune system and on inflammation should be further investigated.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4-CD8 Ratio; Cohort Studies; Darunavir; Dideoxynucleosides; Female; HIV Infections; Humans; Inflammation; Italy; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Cholestasis; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones

There are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low-resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa.. The Pediatric Enhanced Surveillance Study enrolled HIV-infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub-distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date.. Of 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight-for-age z-score (WAZ) was -1.7 (interquartile range (IQR):-3.1 to -0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty-four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub-distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds.. We found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.

Topics: Adult; Alkynes; Ambulatory Care Facilities; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; Health Resources; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Medication Adherence; Ritonavir; South Africa; Viral Load

Topics: Anti-HIV Agents; Collagen; Dideoxynucleosides; Glycoproteins; HIV Infections; Humans; Tenofovir

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are antiretroviral drugs often used in the first-line treatment regimen of HIV1 infection worldwide. We report a case of successive gynecomastia and Stevens-Johnson syndrome (SJS) respectively induced by efavirenz and nevirapine in a single patient.. A 16-year-old boy, HIV1-infected since birth, was started on antiretroviral treatment (ART) in August 2015 and was taking a regimen comprising abacavir, lamivudine and efavirenz. In April 2016, when his weight reached 35kg, abacavir was replaced with tenofovir. Bilateral breast enlargement, previously hidden by the patient, was diagnosed two years after the start of ART. History-taking, physical examination and laboratory tests ruled out known causes of gynecomastia, and efavirenz was thus considered the most likely cause. This drug was then withdrawn and replaced with nevirapine in July 2017. Thirty-three days after the patient started nevirapine treatment, a skin rash appeared. Physical examination revealed erythematous macules and flaccid bullae with estimated skin detachment of 10%. There were also conjunctival, buccal and genital lesions. A diagnosis was made of SJS induced by nevirapine. Three months after withdrawal of efavirenz, breast size decreased by 3cm on the left breast and 2cm on the right breast; two months after the SJS, cutaneous sequelae alone persisted, such as diffuse hyperchromic macules.. Recognition of gynecomastia as a side-effect of efavirenz is important to allow the condition to be treated while it is still potentially reversible. Moreover, when efavirenz is replaced, a protease inhibitor should be preferred to nevirapine.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Gynecomastia; HIV Infections; Humans; Lamivudine; Male; Mucositis; Nevirapine; Reverse Transcriptase Inhibitors; Stevens-Johnson Syndrome

A high risk of cardiovascular disease (CVD) is reported for HIV-infected individuals. While a link between abacavir and CVD risk is suggested, an association between abacavir and hypertension remains unclear. This study evaluated hypertension risk with abacavir use in comparison to non-abacavir antiretroviral treatment (ART).. From a nationwide cohort of HIV-infected individuals on their initial ART, 6493 who were free of hypertension at baseline were analyzed. The use of ART was treated as a time-varying covariate measured as a daily unit. Incidence rate of hypertension was calculated, and Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) with 95% confidence interval (CI) of incident hypertension overall and among subgroups.. From the 6493 participants, 24072 person-years (PY) of follow-up were contributed during 2008-2016. The incidence rates of hypertension were 4.6 and 3.6 per 100 PY for abacavir and non-abacavir ART users, respectively. The population attributable fraction of abacavir use on hypertension was 12%. Abacavir exposure did not elevate the risk of hypertension among overall study population [HR, 1.2 (95% CI, 1.0-1.4),. When present, poor ART adherence, requiring prophylactic antibiotics, male sex, and older age may warrant additional concern for hypertension in patients treated with abacavir.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Hypertension; Incidence; Male; Middle Aged; Proportional Hazards Models; Republic of Korea; Risk Factors

A prediction model for pretreatment HIV RNA level ≤100,000 copies/ml would provide a useful tool for selection of abacavir (ABC) or rilpivirine (RPV) in the first-line regimen in a resource-limited setting. Factors associated with pre-treatment HIV RNA ≤100,000 copies/ml were determined from a cohort of 1,223 patients divided into a derivation (n = 873) and the remaining in a validation group. Their median [interquartile range (IQR)] age was 36.3 (30.5-42.9) years, CD4 count 122 (39-216) cells/mm3 and pre-treatment HIV RNA level 100,000 (32,449-229,777) copies/ml. Factors associated with pretreatment HIV RNA ≤100,000 copies/ml were non-anemia [odds ratio (OR)= 2.05; 95% confidence interval (CI): 1.28-3.27, p= 0.003], CD4 count ≥200 cells/mm3 (OR= 3.00; 95% CI: 2.08-4.33, p<0.001) and non-heterosexual HIV exposure (OR= 1.61; 95% CI: 1.07-2.43, p= 0.021). The area under a receiver operating characteristic curve was 0.66 (95% CI: 0.62-0.69), but specificity was 97.3%. The prediction model identified a set of readily available clinical data but lacked the requisite predictive performance to fulfill its purpose.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; RNA, Viral; Thailand

HLA-B*57:01 is strongly associated with severe adverse drug reaction induced by the anti-HIV drug abacavir (ABC) and antibiotic flucloxacillin. This study was dedicated to establishing a new method for HLA-B*57:01 genotyping and investigating the HLA-B*57:01 distribution pattern in four Chinese populations. A single-tube duplex real-time polymerase chain reaction (PCR) system was established by combining the amplification refractory mutation system and TaqMan probe. The reliability of this assay was validated by comparing the genotyping results with those by sequence-based typing. With this assay, the distribution of HLA-B*57:01 in 354 blood samples from four ethnic groups, namely, Han, Tibetan, Uighur, and Buyei, was determined. A 100% concordance was observed between the results of real-time PCR and sequence-based typing in 50 Uighur samples. As low as 0.016 ng DNA that carried HLA-B*57:01 could be detected with this assay. HLA-B*57:01 carriers identified in 100 Northern Han Chinese, 104 Buyeis, 100 Tibetans, and 50 Uighurs were 0, 1 (0.96%), 3 (3%), and 6 (12%), respectively. The carrier rate of HLA-B*57:01 in Uighur was significantly higher than those in Northern Han (p = .001) and Buyei (p = .005). The newly established real-time PCR assay provides a rapid and reliable tool for HLA-B*57:01 allele screening before the prescription of ABC and flucloxacillin in clinical practice.

Topics: Asian People; Cohort Studies; Dideoxynucleosides; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; Genotype; Genotyping Techniques; HIV Infections; HLA-B Antigens; Humans; Multiplex Polymerase Chain Reaction; Real-Time Polymerase Chain Reaction; Time Factors

HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.. We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.. Subtype B patients ( n  =   3410) were mostly MSM (78%) and those with subtype C ( n  =   810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P  <   0.001).. Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Genetic Association Studies; Genotype; HIV Infections; HIV-1; Humans; Male; Multivariate Analysis; Mutation; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Stavudine; Tenofovir

A survey of 461 HIV-infected Kenyan children receiving antiretroviral therapy found 143 (31%) failing virologically. Drug resistance mutations were found in 121; 37 had L74V/I mutations, with 95% receiving abacavir (ABC)-containing regimens. L74V/I was associated with current ABC usage (P = 0.0001). L74V/I may be more prevalent than previously realized in children failing ABC-containing regimens, even when time on treatment has been short. Ongoing rigorous pediatric drug resistance surveillance is needed.

Topics: Anti-HIV Agents; Child; Child, Preschool; Cross-Sectional Studies; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Kenya; Treatment Failure

The presence of the HLA-B*57:01 allele in HIV-infected subjects is associated with a higher risk of abacavir-associated hypersensitivity reaction (ABC HSR). HLA-B*57:01 allele prevalence varies in different populations, but HLA-B*57:01 testing with immunological confirmation has had a negative predictive value for ABC HSR between 97 and 100%.. In the ASSURE study (EPZ113734), the HLA-B*57:01 prevalence in virologically suppressed, antiretroviral treatment-experienced, HIV-infected subjects from the United States, including Puerto Rico, was assessed.. Three hundred eighty-five subjects were screened; 13 were HLA-B*57:01 positive and 372 were negative. Only HLA-B*57:01-negative, abacavir-naive subjects were eligible to enroll into the ASSURE trial. Eleven of the 13 subjects who possessed the HLA-B*57:01 allele were white, the other 2 were African-American. There was no geographic clustering of HLA-B*57:01-positive subjects, and the incidence correlated roughly with those states with the greatest numbers of subjects screened. Similarly, there was no statistically significant correlation between subjects who possessed or lacked the allele and age, gender, ethnicity or CD4+ T-cell numbers. The incidence of ABC HSR following abacavir initiation was also evaluated. Only 1 of 199 HLA-B*57:01-negative subjects (an African-American male) randomized to receive abacavir-containing treatment developed symptoms consistent with suspected ABC HSR; ABC HSR was not immunologically confirmed.. These findings confirm the utility of HLA-B*57:01 allele testing to reduce the frequency of ABC HSR. The prevalence of HLA-B*57:01 positivity was higher in white than in African-American subjects. In HLA-B*57:01-negative subjects, suspected ABC HSR is very rare, but should lead to discontinuation of abacavir when ABC HSR cannot be definitively excluded from the differential diagnosis.. The ASSURE (EPZ113734) study was registered on ClinicalTrials.gov registration on April 8th 2010 and the registration number is NCT01102972.

Topics: Adult; Anti-HIV Agents; Black or African American; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; United States; White People

We studied the relationships between plasma and saliva concentrations of antiretroviral drugs to explore whether saliva can be used for therapeutic drug monitoring (TDM).. Abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in plasma and saliva from 30 HIV-1-infected patients were quantified using liquid chromatography-tandem mass spectrometry.. Mean saliva-to-plasma concentration ratios were 0.623 (ABC), 0.024 (TFV), 0.065 (DRV), and 0.0135 (RAL), which agree with the plasma protein binding rates except TFV. Significant correlations were evident between saliva and plasma concentrations of ABC, DRV, and RAL.. This study suggests that plasma concentrations of ABC, DRV, and RAL can be estimated from their saliva concentrations and that the saliva concentration of some antiretroviral drugs reflects the unbound drug concentration in plasma.
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Topics: Adult; Aged; Anti-HIV Agents; Chromatography, Liquid; Darunavir; Dideoxynucleosides; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Protein Binding; Raltegravir Potassium; Saliva; Tandem Mass Spectrometry; Tenofovir

Despite a poor toxicity profile, zidovudine supersedes abacavir (ABC) as an alternative first-line agent in most international treatment guidelines because of concerns about HLA-B*57:01-related ABC-hypersensitivity. We detected one case of HLA-B*57:01 carriage among 513 HIV-infected individuals in Uganda, which, in combination with previous reports, supports the safety of ABC in the region.

Topics: Adult; Africa South of the Sahara; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Female; Follow-Up Studies; Genotyping Techniques; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Pilot Projects; Viral Load

The current World Health Organization guideline for first line antiretroviral therapy (ART) in HIV-infected children recommends the use of abacavir and lamivudine as nucleoside backbones and no longer includes stavudine. We compared treatment outcomes with abacavir (ABC) versus stavudine (d4T) in a cohort of HIV-1 infected children 6 and 12 months after antiretroviral therapy was initiated.. This was a retrospective case-cohort study, using programmatic data from children enrolled in the Paediatric Wellness Programme at the Perinatal HIV Research Unit in Soweto, South Africa between 2005 and 2013. Children on abacavir/stavudine who had initiated ART at age <3 years with a regimen including lamivudine and lopinavir/ritonavir and had at least one 6 or 12 month viral load result were eligible. All ABC cases identified were matched for age at ART initiation and gender to eligible d4T controls (1:2). Outcomes analysed at 6 and 12 months post ART initiation included virological failure, mortality, immunological failure and anthropometry. Chi-square tests compared categorical measures while Kruskal-Wallis compared continuous measures.. We identified 57 eligible ABC cases and selected 114 matched d4T controls. Overall, 57% were females and 89% started treatment at age <1year. The median age at ART initiation was 3.11 (IQR: 1.98-6.05) months. There was no difference in the proportion of children virologically suppressed between the groups at 6 (ABC 54.5% vs. d4T 67.0%, p = 0.125) and 12 (ABC 66.7% vs. d4T 71.6%, p = 0.53) months post ART-initiation. The proportion of children with adherence levels >90% for ABC and d4T were similar too (95% in ABC vs. 86% in d4T, p = 0.10). The proportion of children who died over 12 months was 3.5% in the ABC and 7.9% in the d4T group (p = 0.27). Similarly, the anthropometric measures were comparable.. It is reassuring that in the short term, in this group of patients, the treatment outcomes were similar.

Topics: Child, Preschool; Dideoxynucleosides; Drug Combinations; Female; HIV; HIV Infections; Humans; Infant; Lamivudine; Lopinavir; Male; Retrospective Studies; Ritonavir; South Africa; Stavudine; Treatment Outcome; Viral Load

Abacavir is an effective antiretroviral drug and one of the most commonly used nucleoside reverse transcriptase inhibitors in Serbia. А percentage of the treated patients experience a potentially life-threatening hypersensitivity reaction, which was shown to be associated with the presence of the class I MHC allele, HLA-B*57:01; hence genotyping for HLA-B*57:01 prior to starting abacavir is nowadays recommended in international HIV treatment guidelines. In Serbia, this testing became available in 2013. This study was designed to estimate the prevalence of the HLA-B*57:01 allele in Serbian HIV-1-infected patients. The presence of the HLA-B*57:01 allele was analyzed in 273 HIV-1-infected patients aged 18 years or more, who were abacavir naïve. Buccal swab samples were obtained from all participants and assayed for the presence of HLA-B*57:01 using a commercially available HLA-B*57:01 real-time PCR kit. The presence of the HLA-B*57:01 allele was found in 22 of 273 tested individuals (8%; 95% CI 5.4-11.9%). This is the first study that estimated the HLA-B*57:01 prevalence among HIV-infected patients in Serbia. The very high prevalence of HLA-B*57:01 found in our study strongly supports HLA-B*57:01 genotyping, which should be implemented prior to the initiation of an abacavir-containing therapy to reduce the risk of potentially life-threatening hypersensitivity reactions.

Topics: Adult; Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; Genotyping Techniques; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Serbia; Young Adult

There is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates.. Using an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models.. Over 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline.. Current, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors.

Topics: Acute Disease; Adult; Anti-Retroviral Agents; Cohort Studies; Databases, Factual; Dideoxynucleosides; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk Factors; United States

We report this case to highlight the possibility of a severe hypersensitivity reaction as an important potential consequence of couples, living with HIV, sharing anti-retroviral treatment. An HIV-1 positive and carrier of HLA-B*57:01 allele, treatment experienced man was commenced one pill Regimen Stribild (tenofovir, emtricitabine, elvitegravir and cobicistat) in July 2015. On running short of medication, he admitted to sharing his partner's treatment (Triumeq; abacavir, lamivudine and dolutegravir). On the second occasion, re-introduction resulted in whole body rash 4 h post dose and was associated with fever, respiratory symptoms, headache and vomiting. On examination, he was pyrexic, tachyponeic, tachycardiac and hypotensive. Hypersensitivity to abacavir can cause significant morbidity. Re-challenge can result in a more rapid, severe and potentially life-threatening reaction. This potentially could become an increasing problem with more couples, living with HIV, sharing medication.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; HLA-B Antigens; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

South Africa's paediatric antiretroviral therapy (ART) programme is managed using a monitoring and evaluation tool known as TIER.Net. This electronic system has several advantages over paper-based systems, allowing profiling of the paediatric ART programme over time. We analysed anonymized TIER.Net data for HIV-infected children aged <15 years who had initiated ART in a rural district of South Africa between 2005 and 2014. We performed Kaplan-Meier survival analysis to assess outcomes over time. Records of 5461 children were available for analysis; 3593 (66%) children were retained in care. Losses from the programme were higher in children initiated on treatment in more recent years (P < 0·0001) and in children aged ≤1 year at treatment initiation (P < 0·0001). For children aged <3 years, abacavir was associated with a significantly higher rate of loss from the programme compared to stavudine (hazard ratio 1·9, P < 0·001). Viral load was suppressed in 48-52% of the cohort, with no significant change over the years (P = 0·398). Analysis of TIER.Net data over time provides enhanced insights into the performance of the paediatric ART programme and highlights interventions to improve programme performance.

Topics: Adolescent; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cohort Studies; Databases, Factual; Dideoxynucleosides; Electronic Data Processing; Female; HIV Infections; Humans; Infant; Infant, Newborn; Lost to Follow-Up; Male; Rural Population; South Africa; Stavudine; Sustained Virologic Response; Viral Load

A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART.

Topics: Africa South of the Sahara; Alkynes; Anti-HIV Agents; Attitude to Health; Benzoxazines; Caregivers; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; Humans; Infant; Lamivudine; Linear Models; Logistic Models; Male; Medication Adherence; Multivariate Analysis; Nevirapine; Randomized Controlled Trials as Topic; Stavudine; Surveys and Questionnaires; Uganda; Zambia; Zidovudine

While HIV-2 is a causative agent for AIDS in addition to the better studied HIV-1, there is currently no suitable animal model for experimental studies for HIV-2 infection and evaluating promising drugs in vivo. Here we evaluated humanized mice for their susceptibility to HIV-2 infection and tested a single-pill three drug formulation of anti-retrovirals (NRTIs abacavir and lamivudine, integrase inhibitor dolutegravir) (trade name, Triumeq

Topics: Animals; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Disease Models, Animal; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-2; Humans; Lamivudine; Mice; Mice, Inbred BALB C; Oxazines; Piperazines; Pyridones

Tenofovir could have a direct lipid-lowering effect. The aim of our retrospective study was to investigate changes in cardiovascular risk after switching from a tenofovir-sparing to a tenofovir-containing backbone. Lipid parameters and cardiovascular risk [calculated using 10-years Framingham Risk Score (FRS) and 5-years DAD Risk Score (DRS)] were analysed at baseline and after three months. 273 patients were enrolled. After switching, significant decreases in total cholesterol (TC) (-8.2mg/dl, p < 0.001), LDL (-8.7mg/dl, p < 0.001) and DRS (mean -0.26%, p < 0.001) were observed, while a reduction in FRS was only observed in patients with pre-switch high TC or medium-high (>10%) FRS. Pre-switch factors associated with DRS reduction were higher TC, abacavir, new generation protease inhibitors, while zidovudine predicted an increase of DRS. Our results suggest that the improvement of lipid parameters observed after switching to a tenofovir-containing backbone could lead to a significant reduction in predicted cardiovascular risk, which became more evident in subjects with higher cardiovascular risk.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Male; Middle Aged; Retrospective Studies; Risk Factors; Tenofovir

Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting.. A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics).. At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18).. Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring.

Topics: Adult; Africa South of the Sahara; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Nevirapine; Polymerase Chain Reaction; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Thymidine; Treatment Failure; Viral Load; Zidovudine

There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.. We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.. We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.. While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Follow-Up Studies; HIV; HIV Infections; Humans; Infant; Kaplan-Meier Estimate; Lopinavir; Outcome Assessment, Health Care; Proportional Hazards Models; Ritonavir; South Africa; Stavudine; Withholding Treatment; Zidovudine

Two new 2-benzylpyridin-4-one containing metabolites, aspernigrins C (3) and D (4), together with six known compounds (1, 2, and 5-8), were isolated from the marine-derived fungus Aspergillus niger SCSIO Jcsw6F30. The structures of the new compounds were determined by NMR, MS, and optical rotation analyses. All the isolated compounds were evaluated for their inhibitory activities against infection with HIV-1 SF162 in TZM-bl cells. Malformin C (5) showed the strongest anti-HIV-1 activity with IC50 of 1.4±0.06μM (selectivity index, 11.4), meanwhile aspernigrin C (3) also exhibited potent activity with IC50 of 4.7±0.4μM (selectivity index, 7.5).

Topics: Anti-HIV Agents; Aspergillus niger; Cell Line; Drug Screening Assays, Antitumor; HIV Infections; HIV-1; Humans; Niacinamide; Pyridones

Highly active antiretroviral therapy (HAART); the-current standard of antiretroviral therapy for Human Immunodeficiency Virus (HIV) infected persons, has been documented to drastically, reduce the number of cases of Acquired Immune Deficiency Sypdrome (AIDS). However, adverse. events are a challenge to the use of HAART. This study intends to determine the nature and incidence of suspected advcrse events to prescribed anti retroviral drugs in treatment centers in Ekiti State.. One hundred and twenty participants were enrolled and followed up over a period of six months. At each clinic visit, there was an administration of a detailed interviewer questionnaire that was completed by the attending pharmacist together with the participant. The form is designed to obtain information on the demographics of the patients, WHO clinical stage of their HIV infection, HAART regimen for the patients, and suspected adverse events associated with the antiretroviral drugs used by the patients.. Tenofovir/Lamivudine/Eifavirenz (72.5%), Zidovudinc/Lamiv.udin/Nevirapine (16.7%), Zidovudine/Lamivudiine/ElafIvirenz (6.7%), Tenofovir/ Lamivudine/Nevirapine (3.3%), and Abacavir/ Lamivudine/Nevirapine (0.8%) were the HAART regimens prescribed to the patients. About half (57%) of the participants reported clinical adverse events; 92% of which were reported within two weeks of HAART initiation. Most of the reported adveise events were nausea (14.5%), abdominal discomfort (8.2%), and insomnia (7.5%). A few (6%) of those who reported adverse events required regimen switch or drug substitution.. Antiretroviral drugs exposure often presents with adverse events, an observation similar to other studies. Most of the clinical adverse events were not severe or life threatening.

Topics: Abdominal Pain; Adolescent; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Female; HIV Infections; Humans; Incidence; Lamivudine; Male; Middle Aged; Nausea; Nevirapine; Nigeria; Prospective Studies; Sleep Initiation and Maintenance Disorders; Tenofovir; Young Adult; Zidovudine

With the aging of the population living with HIV, the absolute risk of cardiovascular disease (CVD) is increasing. There is a need to further facilitate the identification of persons at elevated risk in routine practice.. Prospective information was collected on 32,663 HIV-positive persons from 20 countries in Europe and Australia, who were free of CVD at entry into the Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Cox regression models (full and reduced) were developed that predict the risk of a global CVD endpoint. The predictive performance of the D:A:D models were compared with a recent CVD prediction model from the Framingham study, which was assessed recalibrated to the D:A:D dataset. A total of 1010 CVD events occurred during 186,364.5 person-years. The full D:A:D CVD prediction model included age, gender, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, high-density lipoprotein, CD4 lymphocyte count, cumulative exposure to protease- and nucleoside reverse transcriptase-inhibitors, and current use of abacavir. A reduced model omitted antiretroviral therapies. The D:A:D models statistically significantly predicted risk more accurately than the recalibrated Framingham model (Harrell's c-statistic of 0.791, 0.783 and 0.766 for the D:A:D full, D:A:D reduced, and Framingham models respectively; p < 0.001). The D:A:D models also more accurately predicted five-year CVD-risk for key prognostic subgroups.. An updated, easily recalibrated, global CVD-risk equation tailored to HIV-positive persons was developed using routinely collected CVD risk parameters and incorporating markers on immune function (CD4 lymphocyte count), and exposure to antiretroviral therapies. The estimated CVD risk can be used to quantify risk and to guide preventive care.

Topics: Adult; Age Factors; Blood Pressure; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Diabetes Mellitus; Dideoxynucleosides; Female; Genetic Predisposition to Disease; HIV Infections; HIV Protease Inhibitors; Humans; Lipoproteins, HDL; Male; Middle Aged; Models, Statistical; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Assessment; Sex Factors; Smoking

HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Estonia; HIV Infections; HIV-1; Humans; Lamivudine; Male; Mutation; Prevalence; Reverse Transcriptase Inhibitors; Zidovudine

Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C.. Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model.. The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23.. The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Bayes Theorem; Benzoxazines; Canada; Coinfection; Cyclopropanes; Dideoxynucleosides; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hepatitis C; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Risk Factors; Tenofovir

Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction.. We conducted a cohort study in Kaiser Permanente California during 1998-2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid-lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate <60 mL·min·1.73 m).. Among 8154 subjects, 178 had ≥1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P < 0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for ≥1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0).. Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors.

Topics: Adult; Anti-HIV Agents; California; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans; Middle Aged; Risk Factors

The HLA-B*57:01 allele is strongly associated with the hypersensitivity reaction to Abacavir (ABC). Therefore, treatment guidelines recommend that patients initiating ABC are preventively tested for the presence of this allele. To date, four different commercial assays based on the real-time quantitative polymerase chain reaction (Q-PCR) technique are available for the detection of HLA-B*57:01: Duplicα-RealTime Reagent Set HLA-B*57:01 by Euroclone, HLA-B*57:01 Real-TM by Sacace Biotechnologies, COBAS AmpliPrep/COBAS TaqMan HLA-B*57:01 Screening Test by Roche Diagnostic, and HLA-B*57:01 by Nuclear Laser Medicine. The study was carried out to compare the performance of the first three commercially available Q-PCR kits in a routine clinical setting. A total of 98 samples from Policlinico Umberto I Hospital were tested. Results obtained by the Duplicα-RealTime Genotyping kit and AmpliPrep/TaqMan system were 100% concordant. In contrast, genotyping by the HLA-B*57:01 Real-TM kit showed poor agreement with the other systems, that is, 12 out of 33 positive samples were detected as HLA-B*57:01 negative. To confirm the correct genotype of these discordant samples, two additional methods with rapid turnaround times and already implemented into routine clinical practice were used, that is, a PCR-based microsequence-specific primer DNA typing test and a laboratory-developed screening test in Q-PCR. All 12 discordant samples were genotyped as HLA-B*57:01-positive samples using these two additional methods in a single-blinded manner, thus confirming the low sensitivity of HLA-B*57:01 Real-TM test. These findings underline the need to compare results obtained with commercial assays before choosing a test suitable for use in a routine clinical laboratory.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug-Related Side Effects and Adverse Reactions; Female; Genotyping Techniques; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction

Abacavir is currently recommended as a part of first line regimen by National AIDS Control Organization. The objective of this study was to observe the incidence of clinically diagnosed abacavir Hypersensitivity reaction (HSR) among children on abacavir based therapy in the National program. In this observational study, all children started on abacavir were included and HSR reaction was diagnosed clinically as per National guidelines. HLA- B*5701 testing was done in children diagnosed with clinical abacavir HSR. Among 101 children started on abacavir during the study period, 8 [7.9 % (95 % CI 3.5-15.0 %)] children developed clinically diagnosed abacavir HSR. All children with concomitant illness (4/8) were HLA-B*5701 negative. Only 2 (25 %, 2/8) carried HLA-B*5701 allele. Fever with abdominal symptoms as compared to respiratory symptoms were more common in HLA-B*5701 positive cases. Overdiagnosis of clinically diagnosed abacavir HSR is common and could be decreased by treating concomitant illness before starting abacavir.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; India; Male

In March 2008, the D:A:D study published results demonstrating an increased risk of myocardial infarction (MI) for patients on abacavir (ABC). We describe changes to the use of ABC since this date, and investigate changes to the association between ABC and MI with subsequent follow-up.. A total of 49,717 D:A:D participants were followed from study entry until the first of an MI, death, 1 February 2013 or 6 months after last visit. Associations between a person's 10-year cardiovascular disease (CVD) risk and the likelihood of initiating or discontinuing ABC were assessed using multivariable logistic/Poisson regression. Poisson regression was used to assess the association between current ABC use and MI risk, adjusting for potential confounders, and a test of interaction was performed to assess whether the association had changed in the post-March 2008 period.. Use of ABC increased from 10 % of the cohort in 2000 to 20 % in 2008, before stabilising at 18-19 %. Increases in use pre-March 2008, and subsequent decreases, were greatest in those at moderate and high CVD risk. Post-March 2008, those on ABC at moderate/high CVD risk were more likely to discontinue ABC than those at low/unknown CVD risk, regardless of viral load (≤1,000 copies/ml: relative rate 1.49 [95 % confidence interval 1.34-1.65]; >1,000 copies/ml: 1.23 [1.02-1.48]); no such associations were seen pre-March 2008. There was some evidence that antiretroviral therapy (ART)-naïve persons at moderate/high CVD risk post-March 2008 were less likely to initiate ABC than those at low/unknown CVD risk (odds ratio 0.74 [0.48-1.13]). By 1 February 2013, 941 MI events had occurred in 367,559 person-years. Current ABC use was associated with a 98 % increase in MI rate (RR 1.98 [1.72-2.29]) with no difference in the pre- (1.97 [1.68-2.33]) or post- (1.97 [1.43-2.72]) March 2008 periods (interaction P = 0.74).. Despite a reduction in the channelling of ABC for patients at higher CVD risk since 2008, we continue to observe an association between ABC use and MI risk. Whilst confounding cannot be fully ruled out, this further diminishes channelling bias as an explanation for our findings.

Topics: Adult; Anti-HIV Agents; Australia; Dideoxynucleosides; Europe; Female; HIV Infections; Humans; Logistic Models; Male; Medication Therapy Management; Middle Aged; Myocardial Infarction; Odds Ratio; Pharmacovigilance; Practice Patterns, Physicians'; Risk Assessment; Risk Factors; United States

To compare the efficacy, in current clinical practice, of first regimens containing abacavir with lamivudine (ABC/3TC) or tenofovir with emtricitabine (TDF/FTC) in patients with baseline viral load ≥100,000 HIV-1 RNA copies/mL.. Using a prospective cohort, we selected all patients starting a first HIV regimen based either on ABC/3TC or on TDF/FTC. The propensity score (PS) method was used to limit the indication bias due to the observational nature of the data. Adjusting and weighting methods via PS were used to compare the effectiveness of a first regimen containing ABC/3TC or TDF/FTC. The primary outcome was treatment failure by month 12 (M12).. Overall, 2781 patients started an antiretroviral (ARV) regimen with ABC/3TC or TDF/FTC each in combination with efavirenz, boosted atazanavir or boosted darunavir. Among the 2472 uncensored patients before M12, 962 (39%) had a baseline viral load ≥100,000 copies/mL of whom 294 were in treatment failure at or before M12. Our analyses showed no difference between ABC/3TC and TDF/FTC in the risk of treatment failure at M12 in patients starting an ARV regimen with a high viral load (≥100,000 copies/mL).. Using a large prospectively collected cohort of patients seeking care in France, we found no evidence that ABC/3TC based regimens led to more failures than TDF/FTC based ones in patients with high baseline viral loads.

Topics: Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; France; HIV Infections; Humans; Lamivudine; Male; Propensity Score; Prospective Studies; Risk Assessment; Tenofovir; Treatment Failure; Viral Load

Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

Topics: Adult; Alanine Transaminase; Biomarkers; Blood Platelets; CD4-Positive T-Lymphocytes; Cell Count; Coinfection; Dideoxynucleosides; Female; Genotype; Hemoglobins; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

The aim of the study was to investigate the in vivo effect of abacavir (ABC) on platelet oxidative stress.. We performed a randomized pilot study including 39 HIV-1-infected patients, 17 on zidovudine/lamivudine (ZDV/3TC) and 22 on tenofovir/emtricitabine (TDF/FTC). Ten patients on ZDV/3TC and eight patients on TDF/FTC were randomly allocated to switching the nucleoside backbone to ABC/3TC. At baseline and after 6 months, platelet oxidative stress was assessed by platelet NADPH oxidase 2 (NOX2)-derived peptide (sNOX2-dp), a marker of NOX2 activation, and platelet prostaglandin F

Topics: Adolescent; Adult; Anti-HIV Agents; Blood Platelets; CD40 Ligand; Dideoxynucleosides; Dinoprost; Female; HIV Infections; Humans; Male; Membrane Glycoproteins; Middle Aged; NADPH Oxidase 2; NADPH Oxidases; Pilot Projects; Platelet Activation; Young Adult

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Interactions; Drug Resistance, Viral; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine, Rilpivirine, Tenofovir Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Mental Disorders; Oxazines; Piperazines; Pyridones; Viral Load

The aim of the study was to evaluate in human immunodeficiency virus (HIV)-infected patients estimated glomerular filtration rate (eGFR) trajectories during treatment with different protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus tenofovir (TDF) or abacavir (ABC) and lamivudine or emtricitabine (xTC).Retrospective study of patients followed at a single clinical center; all patients who started TDF or ABC for the first time with a NNRTI or lopinavir/r (LPV/r) or atazanavir/r (ATV/r) or darunavir/r (DRV/r), for whom at least 1 eGFR value before the start and during the studied treatment was known, were included in this analysis. eGFR was calculated by means of the CKD-EPI formula. Univariate and multivariate mixed linear model (MLM) was applied to estimate eGFR slope with the considered antiretroviral treatment.In the 1658 patients treated with TDF/xTC (aged 43 [37-48] years, with an eGFR of 105 [96; 113] mL/min/1.73 m, 80% males, 92% Caucasians, 10% coinfected with HCV, 4% with diabetes, 11% with hypertension, 38% naive for antiretroviral therapy (ART), 37% with HIV-RNA <50 copies/mL) the median follow-up was 2.5 (1.2-4.6) years. Their adjusted eGFR slopes (95% CI) were -1.26 (-1.58; -0.95), -0.43 (-1.20; +0.33), -0.86 (-1.28; -0.44), and -0.20 (-0.42; +0.02) mL/min/1.73 m per year in patients treated with ATV/r, DRV/r, LPV/r, and NNRTI, respectively. Patients receiving ATV/r or LPV/r had a greater adjusted decline in eGFR compared with those receiving NNRTIs (difference -1.06 [-1.44; -0.69] mL/min/1.73 m per year, P <0.001; and -0.66 [-1.13; -0.20] mL/min/1.73 m per year, P = 0.005, respectively); adjusted eGFR slopes were similar in patients receiving DRV/r and in those receiving NNRTIs. Patients receiving ATV/r had a greater adjusted eGFR decline than those treated with DRV/r (difference -0.83 [-1.65; -0.02] mL/min/1.73 m per year; P = 0.04), but not than those receiving LPV/r; no significant difference was observed in adjusted eGFR slopes between patients receiving DRV/r and those receiving LPV/r. In the 286 patients treated with ABC and lamivudine, eGFR slopes were similar, independent of the PI.In patients receiving TDF/xTC, eGFR trajectories were small for all regimens and declined less in patients receiving DRV/r or NNRTIs than in those treated with ATV/r or LPV/r.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Comorbidity; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Data on pediatric treatment outcomes and drug resistance while on second-line antiretroviral therapy (ART) are needed to guide HIV care in resource-limited countries.. HIV-infected children <18 years who were switched or switching to second-line ART after first-line failure were enrolled from 8 sites in Indonesia, Thailand, and Vietnam. Genotyping was performed at virologic failure (VF; HIV-RNA >1000 copies/mL). Cox proportional hazards regression was used to evaluate factors predicting VF.. Of 277 children, 41% were female. At second-line switch, age was 7.5 (5.3-10.3) years, CD4 count was 300 (146-562) cells per cubic millimeter, and percentage was 13 (7-20%); HIV-RNA was 5.0 (4.4-5.5) log10 copies per milliliter. Second-line regimens contained lamivudine (90%), tenofovir (43%), zidovudine or abacavir (30%), lopinavir (LPV/r; 91%), and atazanavir (ATV; 7%). After 3.3 (1.8-5.3) years on second-line ART, CD4 was 763 (556-1060) cells per cubic millimeter and 26% (20-31%). VF occurred in 73 (27%), with an incidence of 7.25 per 100 person-years (95% confidence interval [CI]: 5.77 to 9.12). Resistance mutations in 50 of 73 children with available genotyping at first VF included M184V (56%), ≥1 thymidine analogue mutation (TAM; 40%), ≥4 TAMs (10%), Q151M (4%), any major LPV mutation (8%), ≥6 LPV mutations (2%), and any major ATV mutation (4%). Associations with VF included age >11 years (hazard ratio [HR] 4.06; 95% CI: 2.15 to 7.66) and HIV-RNA >5.0 log10 copies per milliliter (HR 2.42; 95% CI: 1.27 to 4.59) at switch and were seen more commonly in children from Vietnam (HR 2.79; 95% CI: 1.55 to 5.02).. One-fourth of children developed VF while on second-line ART. However, few developed major mutations to protease inhibitors.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Indonesia; Lamivudine; Male; Prospective Studies; Ritonavir; Thailand; Treatment Outcome; Vietnam; Viral Load; Zidovudine

A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability.. Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice.. MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks.. MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.

Topics: Animals; Anti-HIV Agents; Cell Line; Delayed-Action Preparations; Dideoxynucleosides; Drug Liberation; Half-Life; HIV Infections; HIV-1; Humans; Hydrophobic and Hydrophilic Interactions; Injections, Intramuscular; Macrophages; Male; Mice; Nanoparticles; Particle Size; Poloxamer; Prodrugs; Ritonavir

The pharmacogenetics approach to screen for the presence of the HLA-B*57:01 allele in HIV-1 infected patients is mandatory to prevent the potential development of hypersensitivity reaction to abacavir treatment. Given the limitations of current genotype methodologies, commercial real-time PCR assays were specifically developed for this purpose, but have not been sufficiently validated and are still not widely used. Here, in the context of the HIV laboratory, we assessed the ability of two commercial kits, the LightSNiP rs2395029 HPC5 assay (TIB Molbiol) and the Duplicα

Topics: Adult; Alleles; Anti-HIV Agents; Clinical Laboratory Techniques; Dideoxynucleosides; False Positive Reactions; Genotype; HIV Infections; HLA-B Antigens; Humans; Reagent Kits, Diagnostic; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

Tenofovir disoproxil fumarate (TDF)-associated renal dysfunction may abate when TDF is replaced with abacavir (ABC). The extent to which the third drug atazanavir contributes to renal dysfunction is unclear.. A retrospective analysis was conducted on adults who had plasma viral load (pVL)<200 copies/mL for≥six months while receiving TDF/lamivudine (3TC) - or TDF/emtricitabine (FTC)-based antiretroviral therapy (ART), then switched to ABC/3TC while retaining the third drug in the ART regimen. CD4, pVL, creatinine, estimated glomerular filtration rate (eGFR), serum phosphorus, urine albumin to creatinine ratio and serum lipids were compared between pre-switch baseline and 3, 6 and 12 months after the switch to ABC.. A total of 286 patients switched from TDF to ABC between 2004 and 2014: 232 (81%) male, median age 48 years (interquartile range (IQR) 42, 56). The third drug was atazanavir (± ritonavir) in 141 (49%) cases. The pVL was<50 copies/mL in 93 to 96% at all time points. Median serum creatinine was 93 µmol/L (IQR 80-111) at baseline and decreased to 88 µmol/L (IQR 78-98) at 12 months after the switch to ABC. Median eGFR increased from 74 (IQR 60-88) mL/min at baseline to 80 mL/min (IQR 69-89) at 12 months. Results were not significantly different between patients on atazanavir versus those on another third drug.. Viral suppression was maintained among patients who switched from TDF/3TC or TDF/FTC to ABC/3TC. Serum creatinine and eGFR improved up to 12 months after switching to ABC/3TC, irrespective of whether or not patients were also receiving atazanavir±ritonavir.

Topics: Adenine; Adult; Anti-HIV Agents; Atazanavir Sulfate; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Kidney; Lamivudine; Male; Middle Aged; Retrospective Studies; Ritonavir; Tenofovir; Viral Load

Data on the long-term efficacy and safety of abacavir/lamivudine (ABC/3TC) and nevirapine (NVP) are scarce. This combination has the advantage of simplifying treatment and improving long-term tolerance. The aim of this study was to compare the rate of any discontinuation of antiretroviral (ARV) regimen because of virologic failure (VF), and/or adverse drug reaction (ADR) among patients receiving stable ARV regimens for at least 6 months.ABC/3TC/NVP was compared to ABC/3TC with either ritonavir-boosted darunavir (DRV/r) or ritonavir-boosted atazanavir (ATV/r), unboosted ATV, or tenofovir/emtricitabine (TDF/FTC) with either one of the following: ATV/r, unboosted ATV, DRV/r, efavirenz (EFV), or NVP, in the French prospective multicenter Dat'AIDS cohort.The study enrolled 16,511 patients treated with following ARV regimens: ABC/3TC/NVP (n = 1089), TDF/FTC/NVP (n = 1542), ABC/3TC/DRV/r (n = 1065), ABC/3TC/ATV/r (n = 1847), ABC/3TC/ATV (n = 563), TDF/FTC/ATV/r (n = 3519), TDF/FTC/DRV/r (n = 2767), TDF/FTC/ATV (n = 419), and TDF/FTC/EFV (n = 3700). Mean follow-up was 36 ± 24 months. Patients treated with ABC/3TC/NVP received this regimen as a switch regimen in 97% of cases. By multivariable analysis, the risk of treatment discontinuation due to VF was similar between ABC/3TC/NVP and other ARV regimens, except for TDF/FTC/ATV and ABC/3TC/ATV, which were associated with a higher risk of treatment interruption due to VF (hazard ratio [HR] 1.99; 95% confidence interval [CI] 1.29-3.06 and HR 2.19; 95% CI 1.51-3.18, respectively). Treatment discontinuation due to ADR was lowest with the ABC/3TC/NVP regimen. Other ARV regimens were associated with a 1.80- to 3.19-fold increase in the risk of treatment discontinuation due to ADR (P < 0.0001 for all comparisons).ABC/3TC/NVP as a simplification regimen is a long-term effective regimen with lower discontinuation due to long-term toxicity compared with other standard ARV regimens.

Topics: Adult; Dideoxynucleosides; Drug Therapy, Combination; Female; France; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Prospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome

Incidence of brain infections in Human Immunodeficiency Virus (HIV) positive patients is reduced after the availability of current high active antiretroviral therapy (HAART). Herpes Simplex Virus type 2 (HSV-2) is an infrequent cause of encephalitis in HIV patients despite it is frequently involved in sexual transmitted infections. Here, we report a case of HSV-2 encephalitis occurring in a patient without full suppression of HIV replication within the brain. A 38 year-old HIV infected man was admitted to our department because of recurrent generalized seizure and fever during the previous 24 hours. Eight months before our observation the patient was switched from a protease inhibitor based regimen to a rilpivirine-based regimen without any evidence of HIV-RNA replication in the plasma. When the patient was admitted in our hospital, he was febrile and moderately confused, no deficit of cranial nerves was reported, motility was conserved, but he was unable to walk. Laboratory examinations performed at admission demonstrated an increase of cerebrospinal fluid (CSF) protein and cells with lymphocyte prevalence, and normal CSF glucose. HSV-2-DNA and HIV-RNA were present within CSF at admission. Nuclear Magnetic Resonance imaging of the brain revealed lesions of the medial part of both temporal lobes including hippocampus without any sign of bleeding. A 21-day course of acyclovir therapy was administered with consistent improvement of clinical findings and disappearance of HSV-2-DNA within CSF. After the episode, HAART was switched to a regimen with high CSF penetrability containing abacavir, lamivudine, darunavir and ritonavir. Twelve months after HSV-2 encephalitis neurologic evaluation was normal, but symptoms of depression were reported, HIV-RNA remained undetectable both in the plasma and CSF, and CD4+ lymphocytes were above 500/μL. No opportunistic infection was reported. Patients switched to regimen well tolerated such those containing rilpivirine, that have poor drug concentration within CSF could be considered at risk for opportunistic infection of the brain. Further larger investigation needs to confirm this finding.

Topics: Acyclovir; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Drug Substitution; Encephalitis, Herpes Simplex; Herpesvirus 2, Human; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Rilpivirine; Ritonavir; Virus Replication

Deaths related with human immunodeficiency virus (HIV) infections have been decreased by the introduction of combined anti-retroviral therapy (ART) into the clinical practice. Combined ART usually consists of two nucleoside/nucleotide analogs reverse transcriptase inhibitors (NRTI) that is called backbone and a third drug that belongs to either non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), integrase strand transfer inhibitors (INSTI) or entry inhibitors. During abacavir therapy which is a member of NRTI, hypersensitivity reactions can occur approximately 4-9% of the patients that lead difficulties for the management of HIV infections. It is known that, the development of hypersensitivity reactions to abacavir is strongly associated with the presence of HLA-B*57:01 allel, therefore, HLA-B*57:01 screening should be performed prior to abacavir use. Since there is no data on HLA-B*57:01 prevalence in HIV-1-infected cases in Turkey, this is the first study that screened HLA-B*57:01 allels among HIV-1 infected adults in Turkey. A total of 100 HIV-1-infected patients (81 male, 19 female; mean age: 42.31±11.97 years) who have admitted to the Department of Infectious Diseases and Clinical Microbiology of Ondokuz Mayıs University School of Medicine, Samsun, Turkey, were included in the study. Genomic DNAs were isolated from the blood samples of patients by using a commercial spin column procedure (QIAamp® DNA Blood Mini Kit; QIAGEN GmbH, Germany). HLA-B*57:01 genotyping was performed by the method of sequence-specific primer (SSP)-based amplification using a commercial OlerupSSP® HLA-B*57:01 high-resolution test kit (Olerup SSP AB, Sweden) according to the manufacturer's protocol. The products of polymerase chain reaction were electrophoresed on a 2% agarose gel stained with Olerup SSP GelRed dye (Olerup SSP AB, Sweden), and the bands were evaluated under UV light. In our study, three (2 male, 1 female) out of 100 patients were found positive for HLA-B*57:01 gene with a prevalence of 3%, which is a moderate level. Although the medical usefulness of HLA-B*57:01 screening before the abacavir therapy is emphasized, it was also noted that this application is not cost-effective for the populations with low HLA-B*57:01 prevalence, in contrast to populations with high prevalence. Considering of the incidence of HIV/AIDS in Turkey which is 0.12, the value and cost-effectiveness of HLA-B*57:01 screening in HIV-1 positive cases

Topics: Adult; Alleles; Anti-Retroviral Agents; Dideoxynucleosides; Female; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Prevalence; Reverse Transcriptase Inhibitors; Turkey

Proximal renal tubular dysfunction (PRTD) of varying severity has been associated with antiretroviral toxicity, especially related to the use of tenofovir (TDF). The aim of this study was to investigate whether HIV-infected patients who use a tenofovir-based regimen are at increased risk of tubular dysfunction. We conducted an observational, comparative, longitudinal, prospective study. Estimated glomerular filtration rate (eGFR) and markers of tubular damage to assess tubular dysfunction (fractional excretion of phosphate and uric acid, glycosuria, and proteinuria) were measured at baseline and at weeks 12 and 24. Of 111 participants, PRTD was found in 6.3% at week 12 and 9% at week 24, with no statistically significant difference between those on an abacavir (ABC)-containing regimen or a TDF-containing regimen. We also found an increase in triglycerides associated with the ABC-containing regimen compared with the TDF group. The use of an ABC- or TDF-containing regimen was independently associated with tubular dysfunction, but we found no significant differences between these groups, except when TDF was combined with a protease inhibitor. A better and more complete assessment of renal function is needed, because the presence of tubular dysfunction and proteinuria without impairment of eGFR may affect the renal safety of HIV-infected patients.

Topics: Adenine; Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Tubules, Proximal; Longitudinal Studies; Male; Mexico; Middle Aged; Organophosphonates; Prospective Studies; Protease Inhibitors; Proteinuria; Tenofovir

One of the most successful applications of pharmacogenetics research is the genetic screening for HLA-B*57:01, strongly associated with an increased risk to develop hypersensitivity reaction in HIV-positive patients following abacavir administration. Taking into consideration the limits of current genotyping methodologies, we have developed and validated (150 buccal swabs) an inexpensive pharmacogenetic approach for HLA-B*57:01 typing. In our assay DNA extraction and amplification are combined in one single step (direct PCR protocol), which is performed directly on the biological sample without the need of extraction and sequencing passages. The amplicons obtained by direct PCR can be easily separated on the agarose gel under ultraviolet. As per our results, the direct PCR represents a good alternative to the traditional methods of HLA-B*57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable. Furthermore it is an innovative approach, promoting a personalized, safer and cost-effective therapy.

Topics: Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors

Abacavir (ABC) is one of the more affordable antiretroviral drugs used for controlling HIV. Although with similar efficacy to current first-line drugs, its limited usage in Singapore can be attributed to its possible side effect of adverse hypersensitivity reactions (HSRs). HLA-B*5701 genotyping is a clinically relevant procedure for avoiding abacavir-induced HSRs. As patients who do not carry the risk allele are unlikely to develop HSRs, a simple rule can be developed to allow abacavir prescription for patients who are B*5701 negative. Here, we carry out a cost-effectiveness analysis of HLA-B*5701 genotyping before abacavir prescription in the context of the Singapore healthcare system, which caters predominantly to Han Chinese, Southeast-asian Malays, and South-asian Indians. In addition, we aim to identify the most cost-effective treatment regimen for HIV patients.. A decision tree model was developed in TreeAge. The model considers medical treatment and genotyping costs, genotyping test characteristics, the prevalence of the risk allele, reduction in the quality of life, and increased expenditure due to side effects and other factors, evaluating independently over early-stage and late-stage HIV patients segmented by drug contraindications.. The study indicates that genotyping is not cost-effective for any ethnicity irrespective of the disease stage, except for Indian patients with early-stage HIV who are contraindicated to tenofovir.. Abacavir (as first-line) without genotyping is the cheapest and most cost-effective treatment for all ethnicities except for early-stage Indian HIV patients contraindicated to tenofovir. The HLA-B*5701 frequency, the mortality rate from abacavir-induced HSRs, and genotyping costs are among the major factors influencing the cost-effectiveness.

Topics: Adult; Aged; Anti-HIV Agents; Cost-Benefit Analysis; Decision Support Techniques; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Drug Prescriptions; Genotyping Techniques; Health Care Costs; HIV Infections; HIV-1; HLA-B Antigens; Humans; Life Expectancy; Middle Aged; Practice Patterns, Physicians'; Singapore

The antiretroviral (ARV) pregnancy registry, an international voluntary registry, provides information on teratogenicity and non-defect adverse pregnancy outcomes.. We analyzed ARV pregnancy registry prospective singleton pregnancies, estimating frequencies of and risk for nondefect adverse outcomes among HIV-infected women. Prenatal exposures to abacavir (ABC)-containing regimens vs. non-ABC ARV regimens, and lamivudine (3TC)-containing regimens vs. non-3TC regimens were compared.. Of 2006 outcomes with prenatal ABC exposure, 95.6% were live births; 4.4% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had low birth weight (LBW); 11.9% were preterm births. Relative risks comparing exposure to ABC vs. non-ABC ARV regimens were spontaneous abortions 0.92 [95% confidence interval (CI): 0.66 to 1.27], induced abortions 0.84 (95% CI: 0.59 to 1.21), stillbirths 0.59 (95% CI: 0.35 to 1.00), preterm births 0.96 (95% CI: 0.84 to 1.09), and LBW 1.00 (95% CI: 0.90 to 1.13). Of 11,211 outcomes with prenatal 3TC exposure, 95.3% were live births; 4.7% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had LBW; 11.9% were preterm births. The relative risks comparing exposure to 3TC vs. non-3TC ARV regimens were spontaneous abortions 0.63 (95% CI: 0.50 to 0.80), induced abortions 0.54 (95% CI: 0.43 to 0.69), stillbirths 1.25 (95% CI: 0.86 to 1.80), preterm births 0.86 (95% CI: 0.77 to 0.95), and LBW 1.02 (95% CI: 0.93 to 1.12).. ABC-containing and non-ABC ARV regimens have similar risks for non-birth defect adverse pregnancy outcomes. 3TC-containing regimens have lower risk for spontaneous abortions, induced abortions, and preterm births compared with non-3TC ARV regimens, whereas both regimens had similar prevalence and risks for stillbirths and LBW.

Topics: Abortion, Spontaneous; Adolescent; Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Premature Birth; Prospective Studies; Young Adult

To compare changes in gene expression by microarray from subcutaneous adipose tissue from HIV treatment naïve patients treated with efavirenz based regimens containing abacavir (ABC), tenofovir (TDF) or zidovidine (AZT).. Subcutaneous fat biopsies were obtained before, at 6- and 18-24-months after treatment, and from HIV negative controls. Groups were age, ethnicity, weight, biochemical profile, and pre-treatment CD4 count matched. Microarray data was generated using the Agilent Whole Human Genome Microarray. Identification of differentially expressed genes and genomic response pathways was performed using limma and gene set enrichment analysis.. There were significant divergences between ABC and the other two groups 6 months after treatment in genes controlling cell adhesion and environmental information processing, with some convergence at 18-24 months. Compared to controls the ABC group, but not AZT or TDF showed enrichment of genes controlling adherence junction, at 6 months and 18-24 months (adjusted p<0.05) and focal adhesions and tight junction at 6 months (p<0.5). Genes controlling leukocyte transendothelial migration (p<0.05) and ECM-receptor interactions (p = 0.04) were over-expressed in ABC compared to TDF and AZT at 6 months but not at 18-24 months. Enrichment of pathways and individual genes controlling cell adhesion and environmental information processing were specifically dysregulated in the ABC group in comparison with other treatments. There was little difference between AZT and TDF.. After initiating treatment, there is divergence in the expression of genes controlling cell adhesion and environmental information processing between ABC and both TDF and AZT in subcutaneous adipose tissue. If similar changes are also taking place in other tissues including the coronary vasculature they may contribute to the increased risk of cardiovascular events reported in patients recently started on abacavir-containing regimens.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans; Oligonucleotide Array Sequence Analysis; Risk; Subcutaneous Fat; Time Factors; Transcriptome

Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.. To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.. Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.. We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

Topics: Anti-HIV Agents; Cross Reactions; Dideoxynucleosides; Drug Hypersensitivity; Epitopes, T-Lymphocyte; HIV Infections; HLA-B Antigens; Humans; Immunologic Memory; Immunophenotyping; Leukocytes, Mononuclear; Lymphocyte Count; Phenotype; T-Lymphocyte Subsets; Time Factors; Vaccination; Yellow Fever Vaccine

Topics: Adolescent; Anti-HIV Agents; Black or African American; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Oxazines; Pancreatitis, Acute Necrotizing; Piperazines; Pyridones

Tenofovir is involved in accelerated bone mineral density (BMD) loss.. We recently published a hip BMD improvement at week 48 [+2.1% (95% CI: -0.6, 4.7) (P = 0.043)] in HIV-infected patients with osteopenia/osteoporosis randomized to switch from tenofovir to abacavir (n = 26), although without reaching statistical significance compared with those who maintained tenofovir (n = 28). Here, we present changes at week 48 in bone markers [C-terminal telopeptide of collagen type 1 (CTX), osteocalcin and procollagen type 1 N propeptide (P1NP)] as well as in circulating levels of three proteins involved in bone regulation [osteoprotegerin, receptor activator for NF-κB ligand (RANKL) and sclerostin, a selective regulator of bone formation through the Wnt pathway] in 44 of these patients. χ(2) or Fisher and Student t-tests were performed according to the distribution of the variables.. Bone markers decreased only in the abacavir group [mean (SD) CTX changed from 0.543 (0.495) to 0.301 (0.306) ng/mL; mean (SD) osteocalcin changed from 23.72 (22.20) to 13.95 (12.40) ng/mL; and mean (SD) P1NP changed from 54.68 (54.52) to 28.65 (27.48) ng/mL (P < 0.001 in all cases)], reaching statistical significance between the groups at week 48. Osteoprotegerin did not vary, but sclerostin significantly increased in the abacavir group [from 29.53 (27.91) to 35.56 (34.59) pmol/L, P = 0.002]. No significant differences in osteoprotegerin and sclerostin were detected between the groups at week 48. RANKL values were below the limit of detection in all samples.. The switch from tenofovir to abacavir seems to induce a positive effect on bone tissue, since bone turnover markers decreased. In addition, circulating sclerostin levels increased, a change associated with improved bone properties.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Anti-HIV Agents; Biomarkers; Bone Density; Bone Morphogenetic Proteins; Bone Remodeling; Dideoxynucleosides; Female; Genetic Markers; HIV Infections; HIV-1; Humans; Male; Middle Aged; Tenofovir

Abacavir is a nucleoside reverse transcriptase inhibitor used as part of combination antiretroviral therapy in HIV-1-infected patients. Because this drug can cause a hypersensitivity reaction that is correlated with the presence of the HLA-B*57:01 allotype, screening for the presence of HLA-B*57:01 is recommended before abacavir initiation. Different genetic assays have been developed for HLA-B*57:01 screening, each with specific sensitivity, turnaround time and assay costs. Here, a new real-time PCR (qPCR) based analysis is described and compared to sequence specific primer PCR with capillary electrophoresis (SSP PCR CE) on 149 patient-derived samples, using sequence specific oligonucleotide hybridization combined with high resolution SSP PCR as gold standard. In addition to these PCR based methods, a complementary approach was developed using flow cytometry with an HLA-B17 specific monoclonal antibody as a pre-screening assay to diminish the number of samples for genetic testing. All three assays had a maximum sensitivity of >99. However, differences in specificity were recorded, i.e. 84.3%, 97.2% and >99% for flow cytometry, qPCR and SSP PCR CE respectively. Our data indicate that the most specific and sensitive of the compared methods is the SSP PCR CE. Flow cytometry pre-screening can substantially decrease the number of genetic tests for HLA-B*57:01 typing in a clinical setting.

Topics: Alleles; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; DNA Primers; Drug Hypersensitivity; Electrophoresis, Capillary; Flow Cytometry; Gene Expression; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Nucleic Acid Hybridization; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

Hypersensitivity reaction to abacavir (ABC hypersensitivity syndrome, AHS) is strongly associated with the presence of the HLA-B*57:01 allele. This study was designed to estimate the prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients. We analyzed the presence of HLA-B*57:01 allele in 1646 HIV-1 infected patients from different regions of Argentina. This allele was detected in 81 patients; most of them corresponded to patients living in the central region of the country. The prevalence of HLA-B*57:01 was 4.9%, similar to other Caucasian populations and higher than other data reported for South American populations. This strongly supports screening for the presence of HLA-B*57:01 in abacavir treatment of HIV-1 in our country.

Topics: Adult; Alleles; Anti-HIV Agents; Argentina; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Expression; Gene Frequency; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged

Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates.. We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD.. A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk.. Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

Topics: Adult; Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Switzerland

Topics: Anti-HIV Agents; Atazanavir Sulfate; Dideoxynucleosides; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Lamivudine; Oligopeptides; Pyridines; Ritonavir

HIV-infected persons are at increased cardiovascular disease (CVD) risk, but traditional CVD therapies are understudied in this population. Telmisartan is an angiotensin receptor blocker (ARB) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist that improves endothelial function and cardiovascular mortality in HIV-uninfected populations. We assessed the effects of telmisartan on endothelial function in older HIV-infected persons at risk for CVD in a small pilot study.. HIV-infected individuals≥50 years old on suppressive antiretroviral therapy (ART) with ≥1 traditional CVD risk factor received open-label telmisartan 80 mg daily for 6 weeks. Brachial artery flow-mediated dilation (FMD) measured endothelial function. The primary endpoint was 6-week change in maximum relative FMD.. Seventeen participants enrolled; 16 completed all evaluations (88% men, 65% non-White, median age 60 years, CD4+T lymphocyte count 625 cells/mm3). Antiretroviral therapy included 71% protease inhibitor (PI), 29% non-nucleoside reverse transcriptase inhibitor (NNRTI), 29% integrase inhibitor, 65% tenofovir, and 29% abacavir. Cardiovascular disease risk factor prevalence included 76% hyperlipidemia, 65% hypertension, 18% smoking, and 12% diabetes mellitus. After 6 weeks, statistically significant blood pressure changes were observed (systolic-16.0 mmHg, diastolic-6.0 mmHg) without significant changes in FMD. In subset analyses, FMD increased more among abacavir-treated, PI-treated, and non-smoking participants.. No significant FMD changes were observed after 6 weeks of telmisartan therapy; however, abacavir- and PI-treated participants and non-smokers showed greater FMD increases. Additional studies are needed to explore the effects of telmisartan on endothelial function among HIV-infected individuals with traditional CVD and/or ART-specific risk factors.

Topics: Angiotensin II Type 1 Receptor Blockers; Anti-HIV Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Pilot Projects; Risk Factors; Telmisartan

Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells.. An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data.. Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed.. Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response.. These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.

Topics: Anti-HIV Agents; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Protein Binding

Contradicting results on the effect of abacavir (ABC) on hepatitis C virus (HCV) treatment responses in HIV/HCV co-infected patients have been reported. We evaluated the influence of ABC on the response to pegylated interferon (pegIFN) and ribavirin (RBV)-containing HCV treatment in HIV/HCV co-infected patients in a large European cohort collaboration, including data from different European countries.. HIV/HCV co-infected patients were included if they were aged ≥16 years, received pegIFN alfa-2a or 2b and RBV combination treatment and were enrolled in the COHERE cohort collaboration. Logistic regression was used to evaluate the impact of abacavir on achieving a sustained virologic response (SVR) to HCV treatment.. In total 1309 HIV/HCV co-infected patients who had received HCV therapy were included, of whom 490 (37 %) had achieved an SVR. No statistically significant difference was seen for patients using ABC-containing regimens compared to patients using an emtricitabine + tenofovir (FTC + TDF)-containing backbone, which was the most frequently used backbone. In the multivariate analyses, patients using a protease inhibitor (PI)-boosted regimen were less likely to achieve an SVR compared to patients using a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen (OR: 0.61, 95 % CI: 0.41-0.91). The backbone combinations zidovudine&lamivudine (AZT + 3TC) and stavudine&lamivudine (d4t + 3TC) were associated with lower SRV rates (0.45 (0.24-0.82) and 0.46 (0.22-0.96), respectively).. The results of this large European cohort study validate that SVR rates are generally not affected by ABC. Use of d4T or AZT as part of the HIV treatment regimen was associated with a lower likelihood of achieving an SVR.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Coinfection; Dideoxynucleosides; Drug Combinations; Emtricitabine; Europe; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Interferon-alpha; Lamivudine; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin; Tenofovir; Zidovudine

Current abacavir exposure has been reported to be associated with cardiovascular disease. Changes in platelet reactivity could plausibly explain the clinically observed pattern of association.. To determine if platelet reactivity changed following abacavir exposure and whether this effect was reversible on cessation of the drug.. In an open-label, interventional study abacavir, 600 mg daily, was added to a suppressive antiretroviral regimen in 20 adult HIV-positive men. Platelet function, estimated by the phosphorylated vasodilator-stimulated phosphoprotein (P-VASP) assay and through measurement of the expression and shedding of platelet-specific receptors, was assessed at baseline, following 15 days of abacavir and at completion of a 28-day washout period.. The VASP-index decreased significantly from 79.1% [interquartile range (IQR) 47.8-87.6] to 32.6% (IQR -11.5-51.0) following 15 days of abacavir administration (P = 0.010), and returned to baseline levels following the washout period (day 43 =76.3%; IQR 40.7-92.3). There was no change in resting (prostaglandin E1 alone) P-VASP but a slight increase in P-VASP within stimulated platelets (prostaglandin E1 and adenosine diphosphate). Integrin β3 levels decreased significantly [208.5 ng/ml (IQR 177.0-231.1) to 177.5 ng/ml (IQR 151.7-205) P < 0.001] and there was a nonsignificant trend towards decreased soluble glycoprotein VI levels [baseline; 72.5 ng/ml (95% CI 58.3-81.5) vs. day 15; 45.0 ng/ml (95% CI 33.0-98.2) P = 0.79].. Abacavir led to reversible changes in platelet function and structure. The clinical implications of these changes are uncertain; they may represent negative feedback mechanisms in response to an abacavir-associated prothrombotic state.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Male; Middle Aged; Platelet Activation

Nucleoside reverse transcriptase inhibitors (NRTIs) are an integral part of the current antiretroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5'-succinate derivatives (sNRTI). Biodegradability, small particle size, and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2-10, 2-4, and 1-2 μM drug levels, respectively, for single nanodrugs and dual and triple nanodrug cocktails. Nanogel conjugate of lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Infrequent iv injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

Topics: Animals; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; Hep G2 Cells; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mice; Nanogels; Polyethylene Glycols; Polyethyleneimine; Polylysine; Reverse Transcriptase Inhibitors; Zidovudine

Abacavir hypersensitivity is a rare, yet significant adverse reaction that results in a spectrum of physical and laboratory abnormalities, and has been postulated to stem from a variety of aetiological factors. The major histocompatibility complex haplotype human leucocyte antigen (HLA)-B5701 is a significant risk factor in development of hypersensitivity reactions, yet only 55% of HLA-B5701+ individuals develop such reactions, suggesting a multifactorial aetiology. Nevertheless, prospective screening and avoidance of abacavir in these patients has limited adverse events. Within this spectrum of adverse events, abacavir-induced liver toxicity is exceedingly rare and reported events have ranged from mild elevations of aminotransferases to fulminant hepatic failure. We report the case of a 50-year-old Caucasian woman with a history significant for HIV, hepatitis C virus and a HLA-B5701+ status, transferred to our emergency department in a hypotensive state and found to have acute liver failure, acute renal failure and significant rhabdomyolysis following a change of highly active antiretroviral therapy regimen.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Coinfection; Dideoxynucleosides; Female; Hepatitis C; HIV Infections; HLA-B Antigens; Humans; Liver Failure, Acute; Middle Aged; Prospective Studies; Risk Factors

The treatment of HIV disease has led to a new division of management costs by shifting most of the necessary resources from inpatient treatment to outpatient management. Among the initiatives aimed at rationalising the resources available, we compared efficacy, tolerability and pharmacoeconomic impact of different regimes of antiretroviral therapy (ART). The survey covered the first 50 patients, clinically stable and with good viro-immunological response, who switched in June 2012 from an ART based on the triple combination of tenofovir (TDF), emtricitabine (FTC) and a protease inhibitor boosted with ritonavir (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), to a treatment based on abacavir (ABC), lamivudine (3TC) and a PI/r or NNRTI. Of the 50 patients who operated the switch, 39 replaced a PI with nevirapine (NVP), for which the largest group of patients was treated with ABC + 3TC + NVP. On 31 May 2015, all patients completed the observation period of 96 weeks, with a mean observation period of 132 weeks and clinical-laboratory checks every four months. Laboratory analysis revealed an optimal maintenance of viral suppression and absolute and relative number of CD4 + lymphocytes and improving trend of creatinine, proteinuria, serum phosphate and bone alkaline phosphatase. There was a variable effect on lipids, with a drop in triglycerides associated with a modest increase in total cholesterol. Much of the HIV-positive population reporting to our hospitals (>50%) comprises individuals who have for years been in stable viraemic suppression, making a satisfactory immune recovery while in good overall clinical condition. This type of patient was the target of the present survey. At the end of 96 weeks of observation the new regimes were well tolerated and did not lead to viro-immunological or clinical deterioration. Pharmacoeconomic analysis showed better containment of the overall costs. No patient needed to be hospitalised during the observation period.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Ritonavir; Surveys and Questionnaires; Tenofovir; Treatment Outcome

The association between abacavir (ABC) and cardiovascular disease (CVD) risk in HIV-infected individuals is unclear. Putative mechanisms for an effect of ABC on CVD risk including endothelial dysfunction have been proposed; however, a biological mechanism has not been established.. This was a cross-sectional study of HIV-infected subjects with HIV RNA levels <400 copies/ml, who were randomly assigned to ABC or tenofovir (TDF) as initial therapy during a prior clinical trial. A small cohort of subjects on zidovudine (AZT; not randomly assigned) were studied to explore long-term exposure to this agent. All underwent brachial artery ultrasound for flow-mediated dilation (FMD), and D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fasting lipids were measured. Between-arm differences were evaluated by multivariable linear or logistic regression modelling.. There were 148 subjects (46 on ABC, 72 on TDF and 30 on AZT). Demographic characteristics were balanced across the groups except, as expected, AZT-treated participants were older, had higher CD4(+) T-cell counts, and longer antiretroviral therapy duration. After adjusting for age, brachial artery diameter, and treatment duration, FMD was similar in those on ABC (3.9%) and TDF (5.4%; P=0.181). FMD was higher in those on AZT (6.1%; P<0.005). Levels of IL-6, hsCRP and detectable D-dimer were similar between groups.. Among individuals assigned to ABC or TDF in randomized clinical trials there were no significant differences in FMD or markers of inflammation and coagulation. Whether ABC contributes to risk of CVD remains unclear, but our results suggest that endothelial dysfunction, heightened inflammation, and altered coagulation are unlikely to be mechanisms by which the drug could increase CVD risk above that seen with TDF.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; Blood Coagulation; Cardiovascular Diseases; Dideoxynucleosides; Endothelium, Vascular; Female; HIV Infections; Humans; Inflammation; Male; Middle Aged; Organophosphonates; Risk Factors; Tenofovir; Zidovudine

Initiation criteria and pediatric antiretroviral treatment regimens have changed over the past few years in South Africa. We reported worse early virological outcomes associated with the use of abacavir (ABC)-based regimens at 1 large site: here, we expand this analysis to multiple sites in the IeDEA-Southern Africa collaboration.. Data for 9543 antiretroviral treatment-naïve children <16 years at treatment initiation started on either stavudine/lamivudine (d4T/3TC) or ABC/3TC with efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) treated at 6 clinics in Johannesburg and Cape Town, South Africa, were analyzed with χ tests and logistic regression to evaluate viral suppression at 6 and 12 months.. Prevalence of viral suppression at 6 months in 2174 children started on a d4T-based LPV/r regimen was greater (70%) than among 438 children started on an ABC-based LPV/r regimen (54%, P < 0.0001). Among 3189 children started on a d4T-based EFV regimen, a higher proportion (86%) achieved suppression at 6 months compared with 391 children started on ABC-containing EFV regimens (78%, P < 0.0001). Relative benefit of d4T versus ABC on 6-month suppression remained in multivariate analysis after adjustment for pretreatment characteristics, cohort and year of program [LPV/r: odds ratio = 0.57 (confidence interval: 0.46-0.72); EFV: odds ratio = 0.46 (confidence interval: 0.32-0.65)].. This expanded analysis is consistent with our previous report of worse virological outcomes after ABC was introduced as part of first-line antiretroviral treatment in South Africa. Whether due to the drug itself or coincident with other changes over time, continued monitoring and analyses must clarify causes and prevent suboptimal long-term outcomes.

Topics: Adolescent; Anti-HIV Agents; Child; Cohort Studies; Dideoxynucleosides; Female; HIV; HIV Infections; Humans; Male; South Africa; Stavudine; Treatment Outcome; Viral Load

Topics: Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Dideoxynucleosides; HIV Infections; Humans; Liver; Liver Function Tests; Male

HLA-B*57:01 status needs to be determined before initiating abacavir therapy. We developed a pharmacogenetic real-time (Q)-PCR screening test using two sets of sequence specific primers. This test has been implemented into routine clinical practice.. HIV-infected patients admitted at our University Hospital were thus genotyped using the above mentioned test. A panel of 80 DNA samples with a known genotype were used to characterize Q-PCR conditions using different master mixes.. A total of 353 patients were genotyped, detecting 15 (4.25%) HLA-B*57:01 positive carriers. Among the negative patients, 17.2% were treated with abacavir without any hypersensitivity reaction. Using different Q-PCR master mixes, significantly lower cutoff Ct values were found, thus new analytical settings are provided.. The pharmacogenetic test developed in our laboratory for the fast screening of HLA-B*57:01 can be successfully implemented into routine clinical practice. All 16 sequences (including an additional six) currently known for the HLA-B*57:01 allele are detected by sequence specific primers used in this test. The Brilliant II SYBR(®) Green QPCR MM (Stratagene) can safely replace the master mix originally used to develop the test.

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Pharmacogenetics; Real-Time Polymerase Chain Reaction

Abacavir (ABC), a nucleoside-analogue reverse transcriptase inhibitor, is associated with severe hypersensitivity reactions that are thought to involve the activation of CD8+ T cells in a HLA-B*57:01-restricted manner. Recent studies have claimed that noncovalent interactions of ABC with HLA-B*57:01 are responsible for the immunological reactions associated with ABC. However, the formation of hemoglobin-ABC aldehyde (ABCA) adducts in patients exposed to ABC suggests that protein conjugation might represent a pathway for antigen formation. To further characterize protein conjugation reactions, we used mass spectrometric methods to define ABCA modifications in patients receiving ABC therapy. ABCA formed a novel intramolecular cross-linking adduct on human serum albumin (HSA) in patients and in vitro via Michael addition, followed by nucleophilic adduction of the aldehyde with a neighboring protein nucleophile. Adducts were detected on Lys159, Lys190, His146, and Cys34 residues in the subdomain IB of HSA. Only a cysteine adduct and a putative cross-linking adduct were detected on glutathione S-transferase Pi (GSTP). These findings reveal that ABC forms novel types of antigens in all patients taking the drug. It is therefore vital that the immunological consequences of such pathways of haptenation are explored in the in vitro models that have been used by various groups to define new mechanisms of drug hypersensitivity exemplified by ABC.

Topics: Amino Acid Sequence; Blood Proteins; Dideoxynucleosides; HIV Infections; Humans; Molecular Sequence Data; Reverse Transcriptase Inhibitors; Tandem Mass Spectrometry

Abacavir is a nucleoside reverse transcriptase inhibitor indicated for human immunodeficiency virus (HIV) infection. In Japan, Ziagen® (300-mg abacavir sulfate) has been marketed since 1999. To obtain safety data on Ziagen, a mandatory postmarketing surveillance was conducted between September 1999 and September 2009.. A joint survey [HIV-related Drug Surveys (HRD)] has been conducted involving manufacturers of drugs for HIV treatment in Japan. Safety data from total 643 cases (1345.7 person-years) registered to the HRD surveys and received Ziagen were obtained. Adverse drug reaction (ADR) was defined as adverse event of which association with abacavir could not be "ruled out.". It was found that the overall frequency of ADR was 47.6% (306/643); the common ADRs were "hyperlipidemia," "nausea," "increased γ-glutamyltransferase level," "increased blood triglycerides," "abnormal hepatic function," and so on. Serious adverse events were reported in 65 subjects; however, none of the three fatal cases were clearly associated with Ziagen use. The survey-defined hypersensitivity has been infrequently reported in 15 subjects (2.3%). Although some studies had indicated of the association between abacavir and myocardial infarction, no ischemic heart diseases were reported in the present survey. Two of the three pregnant cases delivered normal neonates (one induced abortion).. During the mandatory postmarketing survey of Ziagen, there were no cases of ischemic heart diseases, and the incidence of hypersensitivity was considerably low. These indicated that abacavir can be safely used in Japanese HIV+ population. However, the safety profile of Ziagen should be continued to be monitored through pharmacovigilance.

Topics: Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Japan; Product Surveillance, Postmarketing; Reverse Transcriptase Inhibitors

Women are very much susceptible for acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases (STDs), mainly due to unprotected heterosexual vaginal intercourse and for some other social and economical disadvantages. Our aim was to formulate and optimize vaginal film of abacavir, a potent nucleoside reverse transcriptase inhibitor, for the treatment of AIDS and HIV. Abacavir films were prepared by solvent evaporation method using sodium alginate (Na-alginate) as the main polymer, Hydroxypropyl Methylcellulose E 15 (HPMC E 15) as the copolymer and glycerol as a humectant. Abacavir sulphate (ABC) was used here as a drug. Films were optimized for various physicochemical parameters such as tensile strength, % elongation at break, swelling capacity, drug content (mg/cm(2)), thickness, folding endurance, bioadhesion, pH, moisture content and SEM. Drug polymer interaction was studied by FTIR Spectra. The drug release study was accomplished in dissolution apparatus. In vivo study was also carried out. This newly formed film was one kind of sustain release type and can be considered as a novel drug carrier system for the treatment of AIDS and other STDs. It was suitable for local as well as systemic effect. The films showed good physicochemical property with good aesthetic appeal.

Topics: Acquired Immunodeficiency Syndrome; Alginates; Animals; Anti-HIV Agents; Chromatography, High Pressure Liquid; Dideoxynucleosides; Drug Delivery Systems; Female; Glucuronic Acid; Glycerol; Hexuronic Acids; HIV Infections; Humans; Hydrogen-Ion Concentration; Hypromellose Derivatives; Kinetics; Materials Testing; Microscopy, Electron, Scanning; Rabbits; Spectroscopy, Fourier Transform Infrared; Stress, Mechanical; Tensile Strength; Vagina

The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.. A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.. Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).. Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

Topics: Anti-HIV Agents; Base Sequence; Child; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; pol Gene Products, Human Immunodeficiency Virus; Sequence Analysis, DNA; South Africa; Statistics, Nonparametric; Stavudine

For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.

Topics: Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Pregnancy

Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases.. We plan to do a systematic review to evaluate the antiviral efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV-infected children aged between 3 months and 18 years, compared with other NRTIs. We will search Scopus, Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science databases for eligible studies regardless of language or publication status. We will check the reference lists of included studies, search relevant conference proceedings, email the authors of included studies and also look for unpublished and ongoing trials in prospective clinical trial registries. Two authors will independently screen search outputs, select studies, extract data and assess the risk of bias in included studies. All disagreements will be resolved by discussion and consensus. Where data allow, we will conduct meta-analysis for similar types of participants, study designs, interventions, and outcome measures. If the results are statistically homogeneous, we will use the fixed-effect model; otherwise, we will use the random-effects model and explore the reasons for heterogeneity using subgroup analyses. Heterogeneity will be assessed with the Chi-squared test and quantified with the I-squared statistic.. The findings will be useful to policy makers and programme managers to inform treatment and management of HIV in children and adolescents and to point out research gaps for future research.. This review is registered with PROSPERO, registration number CRD42014009157.

Topics: Adolescent; Child; Child, Preschool; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Infant; Information Storage and Retrieval; Reverse Transcriptase Inhibitors; Review Literature as Topic; Systematic Reviews as Topic; Treatment Outcome

Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.. Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥ 6 months were included. Predictors of treatment failure and treatment modification were assessed.. Data from 4662 eligible patients was analysed. Patients started ART in 2003-2006 (n = 1419), 2007-2010 (n = 2690) and 2011-2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7-23.5] events per 100 patient/years in 2003-2006, 15.8 [14.9-16.8] in 2007-2010, and 11.6 [9.4-14.2] in 2011-2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33-0.81], p = 0.004 for 2011-2013 versus 2003-2006), older age (1.56 [1.19-2.04], p = 0.001 for ≥ 50 years versus <30 years), female sex (1.29 [1.11-1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06-1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28-20.54], p<0.001 for stavudine-based regimens versus tenofovir-based).. The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Asia; Dideoxynucleosides; Drug-Related Side Effects and Adverse Reactions; Female; HIV; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine

To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy.. A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years.. Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions.. This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blepharoptosis; Cyclopropanes; Didanosine; Dideoxynucleosides; DNA, Mitochondrial; HIV Infections; Humans; Male; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Oculomotor Muscles

HLA-B(∗)57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B(∗)57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B(∗)57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B(∗)57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B(∗)57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country.

Topics: Alleles; Anti-HIV Agents; Costa Rica; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Expression; Gene Frequency; Genetic Markers; Heterozygote; HIV Infections; HLA-B Antigens; Humans; Male; Risk Factors

One of the necessary conditions to perform any personalized medicine is to obtain good individual predictions. In addition to the numerous markers available (omics data), the methods used to analyze the data are very important too. We are presenting an example of mathematical dynamical mechanistic model that could be used for adapting the antiretroviral treatment in patients infected by the human immunodeficiency virus. The interest of this type of approach is to build a model based on biological knowledge about the interaction between markers and therefore to allow for a better predictive power.

Topics: Anti-HIV Agents; Azacitidine; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Dideoxynucleosides; HIV Infections; HIV-1; HLA-B Antigens; Humans; Lamivudine; Models, Theoretical; Precision Medicine; Receptors, CCR5; Reverse Transcriptase Inhibitors; Virus Attachment

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Asthenia; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Drug Substitution; Emtricitabine; Female; Fever; HIV Infections; Humans; Lamivudine; Nevirapine; Organophosphonates; Reverse Transcriptase Inhibitors; Syndrome; Tenofovir

Abacavir hypersensitivity is associated with the presence of human leukocyte antigen (HLA)-allele B*5701. However, the cost and workload of routine HLA-B*5701 pretreatment screening is relatively heavy. This study aimed to determine the prevalence of the HLA-B*5701 allele in the HIV-positive population under care in Hong Kong. Blood samples from 1264 HIV-1 infected patients in Hong Kong were collected between 2007 and 2011 for this study. HLA-B*5701 screening of the study group was determined by in-house polymerase chain reaction (PCR) followed by confirmation using the AlleleSEQR(®) HLA-B PCR/Sequencing Kit (Celera Corporation for Abbott, San Francisco, USA). HLA-B*5701 carriers were identified among 3% of Caucasians, 1% of non-Chinese Asians and 0.5% of Han-Chinese in Hong Kong. Our findings revealed that HLA-B*5701 pretreatment screening might not be necessary for the local Han-Chinese population due to its low prevalence.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Asian People; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Hong Kong; Humans; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Young Adult

We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group).. Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA.. A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log₁₀ copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001).. At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; Emtricitabine; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Tenofovir; Thymidine; Treatment Failure; Viral Load; Zidovudine

Abacavir (ABC) has been associated with ischaemic cardiovascular events in HIV-infected patients, but the pathogenic mechanisms are unknown. Aim of our study was to assess whether ABC induces in vivo platelet activation and ex vivo platelet hyper-reactivity. In a retrospective, case-control study, in vivo platelet activation markers were measured in 69 HIV-infected patients, before starting therapy and after 6-12 months of either ABC (n=35) or tenofovir (TDF) (n=34), and compared with those from 20 untreated HIV-infected patients. A subgroup of patients was restudied after 28-34 months for ex vivo platelet reactivity. In vivo platelet activation markers were assessed by ELISA or flow cytometry, ex vivo platelet reactivity by light transmission aggregometry (LTA) and PFA-100®. Thein vitro effects of the ABC metabolite, carbovir triphosphate, on aggregation and intra-platelet cGMP were also studied. sPLA2, sPsel and sGPV increased significantly 6-12 months after the beginning of ABC, but not of TDF or of no treatment. Ex vivo platelet function studies showed enhanced LTA, shorter PFA-100® C/ADP closure time and enhanced platelet expression of P-sel and CD40L in the ABC group. The intake of ABC blunted the increase of intraplatelet cGMP induced by nitric oxide (NO) and acutely enhanced collagen-induced aggregation. Preincubation of control platelets with carbovir triphosphate in vitro enhanced platelet aggregation and blunted NO-induced cGMP elevation. In conclusion, treatment with ABC enhances in vivo platelet activation and induces platelet hyperreactivity by blunting the inhibitory effects of NO on platelets. These effects may lead to an increase of ischaemic cardiovascular events.

Topics: Adenine; Adult; Anti-HIV Agents; Blood Platelets; Case-Control Studies; CD40 Ligand; Cyclic GMP; Deoxyguanine Nucleotides; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Nitric Oxide; Organophosphonates; P-Selectin; Phospholipases A2, Secretory; Platelet Activation; Platelet Aggregation; Retrospective Studies; Tenofovir

Topics: Adolescent; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; Male; Patch Tests; T-Lymphocytes

Low bone mineral density (BMD) is common in HIV-infected patients. We aimed to describe the prevalence of low BMD and risk factors in Korean HIV-infected patients and to assess the effects of antiretroviral therapy (ART) on BMD. We retrospectively evaluated 224 HIV infected-patients. The prevalence of osteopenia and osteoporosis were 41.5% and 12.9%. These were much higher in 53 patients aged 50 yr and older (52.8% and 34.0%). Older age, lower body mass index, and ART > 3 months were independent risk factors for low BMD. Osteoporosis was more prevalent in patients on the abacavir-based regimen for < 1 yr than ≥ 1 yr; however, it was more prevalent in patients on the zidovudine-based regimen for ≥ 1 yr than < 1 yr (P = 0.017). Osteoporosis in patients on the abacavir-based regimen was more common in the spine than in the femur (P = 0.01). Given such a high prevalence of low BMD, close monitoring of BMD for HIV-infected patients on ART is required. The different prevalence of osteoporosis over time and affected areas between two regimens suggest they may play roles in different mechanisms in bone loss.

Topics: Adult; Anti-HIV Agents; Asian People; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Odds Ratio; Osteoporosis; Prevalence; Republic of Korea; Retrospective Studies; Risk Factors; Zidovudine

Concerns about stavudine (d4T) toxicity have led to increased use of abacavir (ABC) in first-line pediatric antiretroviral treatment (ART) regimens. Field experience with ABC in ART-naïve children is limited.. Deidentified demographic, clinical and laboratory data on HIV-infected children initiating ART between 2004 and 2011 in a large pediatric HIV treatment program in Johannesburg, South Africa, were used to compare viral suppression at 6 and 12 months by initial treatment regimen, time to suppression (<400 copies/mL) and rebound (>1000 copies/mL after initial suppression). Adjusted logistic regression was used to investigate confounders and calendar effects.. Two thousand thirty-six children initiated either d4T/3TC- or ABC/3TC-based first-line regimens in combination with either boosted lopinavir (LPV/r) or efavirenz (EFV). 1634 received d4T regimens (LPV/r n = 672; EFV n = 962) and 402 ABC regimens (LPV/r n = 192; EFV n = 210). At 6 and 12 months on ART, viral suppression rate was poorer in ABC versus d4T groups within both the LPV/r and EFV groups (P < 0.0001 for all points). In ABC groups, time to suppression was significantly slower (log-rank P < 0.0001 and P = 0.0092 for LPV/r- and EFV-based, respectively) and time to rebound after suppression significantly faster (log-rank P = 0.014 and P = 0.0001 for LPV/r- and EFV-based, respectively). Logistic regression confirmed the worse outcomes in the ABC groups even after adjustment for confounders.. Data from this urban pediatric ART service program show significantly poorer virological performance of ABC compared with d4T-based regimens, a signal that urgently warrants further investigation.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Female; HIV Infections; Humans; Infant; Male; Retrospective Studies; Treatment Outcome; Viral Load

Antiretroviral medications, specifically tenofovir, have been linked to acute tubular necrosis in humans with a suggested mechanism of direct tubular injury. Rhabdomyolysis has rarely been described in patients on highly active antiretroviral therapy (HAART). To the best of our knowledge, severe recurrent rhabdomyolysis-induced acute kidney injury (AKI) in a HIV-infected patient on two different triple antiretroviral regimens has not been reported. We present a HIV-positive patient who first developed heme pigment-induced oliguric AKI due to non-traumatic rhabdomyolysis, 5 days after initiation of triple antiretroviral therapy. Renal function normalized 2 months after discontinuation of antiretroviral therapy. Two weeks after reinitiating a different HAART regimen, our patient developed a recurrent episode of severe rhabdomyolysis-induced AKI. Both rhabdomyolysis and AKI resolved after discontinuation of the second antiretroviral regimen. First tenofovir and subsequently abacavir seem to be the likely culprits in our case. We also briefly discuss tenofovir nephrotoxicity followed by a literature review on rhabdomyolysis in HIV-infected patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; HIV Infections; Humans; Kidney Tubular Necrosis, Acute; Male; Organophosphonates; Rhabdomyolysis; Tenofovir

The authors had for objective to describe HIV-infected patients treated with ABC (Ziagen(®), ABC), and the immune, virological, and clinical treatment outcome between 2003 and 2008.. We performed a retrospective analysis of the Dat'AIDS database on patients who were treated with ABC for the first time between 2003 and 2008.. Eight hundred and thirty-six patients were included. Before initiation of ABC, 26.3% has stopped the previous treatment because of immuno-virological failure, 30.5% because of adverse events, and 29.8% for other reasons. Thirteen percent were antiretroviral naive. One third of patients were ranked as CDC class C, and more than 2/3 had a viral load<5 log copies/mL or a CD4 count≥200mm(3). ABC was mainly included in a combination containing 2 NRTI and 1 PI (63%), or 1 non-NRTI (16%). Thirty-two percent of patients were still treated with ABC after 2years of treatment and the median of ABC treatment was 11months (IQ 84days-2years). The main causes for stopping ABC were therapeutic simplification (47.4% of patients), intolerance (19.0%), and immuno-virological failure (9.8%). Suspected hypersensitivity reactions were the main cause of discontinuation due to intolerance (27.6%); the rate was 3.8% when ABC had been introduced before the routine use of the screening test HLA-B*5701. The incidence of myocardial infarction was 3.8 per 1000 patient-years; 70.6% of patients received a fixed combination including ABC after discontinuation of ABC as a single agent (Ziagen(®)).. This retrospective analysis confirmed the effectiveness and the good tolerance of ABC in the therapeutic strategy, between 2003 and 2008.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drug Utilization; Electronic Health Records; Female; France; Genetic Predisposition to Disease; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Viremia

The development of HIV resistance mutations reduces the efficacy of specific antiretroviral drugs used to treat HIV infection and cross-resistance within classes of drugs is common. Recursive partitioning has been extensively used to identify resistance mutations associated with a reduced virologic response measured at a single time point; here we describe a statistical method that accommodates a large set of genetic or other covariates and a longitudinal response. This recursive partitioning approach for continuous longitudinal data uses the kernel of a U-statistic as the splitting criterion and avoids the need for parametric assumptions regarding the relationship between observed response trajectories and covariates. We propose an extension of this approach that allows longitudinal measurements to be monotone missing at random by making use of inverse probability weights. We assess the performance of our method using extensive simulation studies and apply them to data collected by the Forum for Collaborative HIV Research as part of an investigation of the viral genetic mutations associated with reduced clinical efficacy of the drug abacavir.

Topics: Biomarkers; Computer Simulation; Data Interpretation, Statistical; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Longitudinal Studies

Human leukocyte antigen (HLA)-B*5701 allele is associated with abacavir hypersensitivity. Limited data among Asians showed lower rates of HLA-B*5701 compared with Caucasians. In 296 children with HIV in Thailand and Cambodia, the prevalence of HLA-B*5701 was 4.0% (95% confidence interval: 1.6-8.0%) among Thai and 3.4% (95% confidence interval: 0.9-8.5%) among Cambodian children. HLA-B*5701 carriage is not uncommon among Thai and Cambodian children; it is close to the prevalence found in European and higher than the prevalence found in East Asian and African studies.

Topics: Cambodia; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA-B Antigens; Humans; Infant; Male; Prevalence; Thailand

To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations.. Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg(-1) day(-1) or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.. A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration-time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l(-1) and 6.1 mg h l(-1) for toddlers and infants, and 3.6 mg l(-1) and 8.7 mg h l(-1) for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling.. The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.

Topics: Adolescent; Age Factors; Anti-HIV Agents; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Dideoxynucleosides; Female; HIV Infections; Humans; Infant; Male; Models, Biological; Sex Factors

Stavudine is a commonly used drug in paediatric antiretroviral treatment (ART) regimens. Due to toxicity concerns, however, the drug abacavir has replaced stavudine in first-line paediatric regimens in many countries. We describe the frequency of stavudine toxicity in children receiving ART at a treatment clinic in Soweto, South Africa.. Data on patient characteristics and outcomes of ART were collected from a cohort of 2222 HIV-infected children initiating ART between 2004 and 2008 when stavudine-containing regimens were routinely recommended. At several time-points after treatment initiation, we estimate the proportion of children where an attending clinician discontinued stavudine due to lipodystrophy, pancreatitis, lactic acidosis or peripheral neuropathy. Factors associated with stavudine-related toxicities were identified.. At ART initiation, most children had advanced disease. The majority initiated an efavirenz/lamivudine/stavudine regimen (n = 1422), and 76% of children remained on their initial ART regimen after a median 19.9 months of ART. Replacement of stavudine due to drug toxicity occurred at a rate of 28.8 per 1000 child years on treatment (95% confidence interval = 23.6-35.2). Rates of toxicity increased with treatment duration (in their first year of ART stavudine was replaced in 0.5% of children, but after 3 years stavudine had been changed to abacavir in 12.6% of children). Toxicity was more common in older children and in girls. Lipodystrophy accounted for 87 of 96 toxic events.. Stavudine-associated toxicity resulting in single-drug substitution was uncommon in this cohort, though its frequency increased steadily with ART duration, especially with lipodystrophy. Where drug options are limited, stavudine remains a relatively well tolerated and effective option for children.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Retrospective Studies; Risk Factors; South Africa; Stavudine; Time Factors

In human immunodeficiency virus-hepatitis C virus (HIV-HCV) co-infected patients, steatosis has been independently associated with a number of antiretroviral drugs, including stavudine, especially in patients with non-3 HCV genotypes. We retrospectively investigated the presence of steatosis among HIV-HCV co-infected and HCV mono-infected patients, and the role of tenofovir disoproxil fumarate (TDF) or abacavir (ABC) in determining hepatic steatosis.. Liver steatosis was retrospectively evaluated in all consecutive biopsies performed in the period 2000-2008 in HCV mono-infected and HIV-HCV co-infected patients. A steatosis rate of >5 % was considered to be significant, and a multivariate logistic analysis was performed to evaluate factors associated with steatosis.. In total, 393 HCV-infected patients underwent liver biopsy during the study period, of whom 205 (52.2 %) were co-infected with HIV. A steatosis rate of >5 % was diagnosed in 33.0 % of HCV mono-infected and in 47.8 % of HIV-HCV co-infected patients (P = 0.003). The rate of steatosis was higher in patients resuming antiretroviral therapy (54.7 %) than in naïve patients (33.3 %; P = 0.006). When the overall population was considered, steatosis was associated to HCV genotype 3 [odds ratio (OR) 4.53, 95 % confidence interval (CI) 2.71-7.58; P < 0.001]. In terms of the use of nucleos(t)ide drugs in HIV co-infected patients, multivariate analysis showed that only in patients with HCV genotypes other than genotype 3 was steatosis related to the use of stavudine (OR 5.38, 95 % CI 1.18-24.53; P = 0.03). The use of TDF (OR 1.07, 95 % CI 0.39-2.88; P = 0.898) or ABC (OR 0.592, 95 % CI 0.09-4.07; P = 0.594) was not associated with steatosis.. In HCV mono-infected and HIV-HCV co-infected patients, steatosis appears to be a virus-mediated effect of HCV genotype 3. In HIV patients infected with HCV genotypes other than genotype 3, the risk of developing steatosis was higher in those patients resuming antiretroviral regimens containing old drugs rather than the new antiretrovirals.

Topics: Adenine; Adult; Anti-HIV Agents; Coinfection; Dideoxynucleosides; Fatty Liver; Female; Genotype; Hepatitis C; HIV Infections; Humans; Liver; Male; Multivariate Analysis; Organophosphonates; Prevalence; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Tenofovir

Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected individuals on cART via inhibition of telomerase activity.. Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART.. Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 μM. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47; P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11; P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01).. NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected individuals on cART.

Topics: Adenine; Adult; Aging; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Case-Control Studies; Cells, Cultured; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Enzyme Activation; Female; HIV; HIV Infections; Humans; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Regression Analysis; Reverse Transcriptase Inhibitors; Risk Factors; Telomerase; Telomere; Telomere Shortening; Tenofovir; Time Factors; Young Adult; Zidovudine

A 48-year old male coinfected by human immunodeficiency virus and hepatitis C virus (HCV) genotype 3a. The patient was under clinically and virologically effective treatment with Trizivir (zidovudine, lamivudine and abacavir) when it was decided to initiate treatment for the chronic HCV infection with peginterferon and ribavirin. Should the ongoing antiretroviral treatment be adjusted?

Topics: Anti-HIV Agents; Antiviral Agents; Coinfection; Dideoxynucleosides; Drug Combinations; Drug Interactions; Hepatitis C, Chronic; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Ribavirin; Zidovudine

Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.

Topics: Adenosine Triphosphate; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Brain; Cells, Cultured; Chemistry, Pharmaceutical; Dideoxynucleosides; Dimerization; HIV Infections; Humans; Inhibitory Concentration 50; Models, Chemical; Prodrugs

Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children.. A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers.. To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy.. The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method.. The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t.. The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC(0-) (t) was developed from the final model and can be used routinely to optimize individual dosing.

Topics: Anti-HIV Agents; Area Under Curve; Bayes Theorem; Body Weight; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; HIV Infections; Humans; Infant; Male; Models, Biological

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

Tenofovir disoproxil fumerate (TDF) is an effective nucleoside reverse transcriptase inhibitor for HIV infection but it is potentially nephrotoxic. A selective mithochondrial toxicity has been hypothesized. To assess early markers of renal toxicity, we evaluated a cohort of antiretroviral (ARV)-experienced HIV patients who had been switched from a thymidinic backbone to either a TDF/emtricitabine regimen (TDF; 73 patients) or an abacavir/lamivudine (ABV) regimen (28 patients). Markers of mitochondrial toxicity (cytochrome c, Cyc) or cytosolic (α-glutathione S transferase, α-GST) together with common indicators of renal damage were assessed at baseline (T0) and after 1 (T1), 3 (T2), 6 (T3), and 12 (T4) months of patient exposure to therapy. Clinical features of both groups were comparable at T0. There was no significant variation in estimated glomerular filtration rate (eGRF), median urine protein excretion, or microalbuminuria and serum phosphate levels in both groups during the study period. There was a significant increase in urinary excretion of phosphate in patients on TDF compared to those on ABV at T3 and T4. Fractional excretion of uric acid was also altered in the two treatment groups; there was no change in the ABV (constantly less than 0.10), but a progressive increase in TDF patients. Serum potassium levels were significantly lower in ABV than in TDF treated patients. Urine concentrations of α-GST showed a nonsignificant variation in both groups, while Cyc excretion was significantly higher at T1 and T3 in TDF-treated compared to ABV-treated patients. In conclusion, TDF may be associated with subclinical mitochondrial damage, inducing at a later stage increased urinary excretion of phosphate and uric acid, as markers of incipient tubular injury.

Topics: Adenine; Anti-HIV Agents; Biomarkers; Cohort Studies; Cytochromes c; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Glomerular Filtration Rate; Glutathione Transferase; HIV Infections; Humans; Kidney Diseases; Kidney Tubules, Proximal; Lamivudine; Male; Middle Aged; Mitochondria; Organophosphonates; Tenofovir; Time Factors

The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)(0-12) and peak concentration (C(max)) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC(0-12) were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC(0-12) dnGMR = 1.58 (1.37-1.81), C(max) dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations.

Topics: Administration, Oral; Antirheumatic Agents; Chemistry, Pharmaceutical; Child, Preschool; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Solutions; Tablets; Therapeutic Equivalency; Zidovudine

The field of pharmacogenetics is witnessing a growing interest in the role of the human leukocyte antigen (HLA) in manifestation of adverse drug reactions (ADR). Here we report a retrospective analysis of the association of HLA-B*5701 with abacavir hypersensitivity syndrome (AHS) in a large Canadian cohort of 489 human immunodeficiency virus-1-positive patients exposed to abacavir. A total of 3.7% of abacavir-exposed patients had developed AHS. Using polymerase chain reaction sequence-specific primer-based genotyping, the HLA-B*5701 allele was observed in 20 patients (4.1%). Of the 20 HLA-B*5701(+) abacavir-treated patients, 18 (90%) had developed AHS. Carriage of the HLA-B*5701 allele indicated a strong association with abacavir hypersensitivity (p < 0.0001; odds ratio = 6,934; 95% confidence interval = 321-149,735). HLA-B*5701 genotyping demonstrated high sensitivity, specificity, and positive and negative predictive values. The data derived from the study highlight the importance of engaging histocompatibility and immunogenetics laboratories in taking a lead in mapping other less characterized HLA and immunogenetic markers associated with ADRs.

Topics: Adult; Aged; Aged, 80 and over; Alberta; Anti-HIV Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Pharmacogenetics; Retrospective Studies

To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection.. We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART.. The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model.. The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152-2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339-3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494-5.139; p = 0.001) (61-68 kg: adjusted HR = 1.908; 95%CI, 0.764-4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318-3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003).. The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.

Topics: Adenine; Adult; Antiretroviral Therapy, Highly Active; Body Weight; Demography; Dideoxynucleosides; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Multivariate Analysis; Organophosphonates; Risk Factors; Tenofovir

This study examined the effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction.. Among the Study to Understand the Natural History of HIV/AIDS in the Era of Effective therapy (SUN) participants, we identified 25 individuals (cases) who were HLA-B5701-negative and who had ≥ 2 weeks without abacavir exposure at one visit and ≥ 2 weeks with abacavir exposure at the consecutive visit while maintaining viral suppression. We identified 43 individuals (controls) similarly unexposed and exposed to tenofovir. We assessed concentrations of prothrombin fragment F(1+2), D-dimer, high-sensitivity C-reactive protein, interleukin-8, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, P-selectin, serum amyloid A and serum amyloid P. We examined the median percentage change of these biomarkers from the unexposed to exposed state among cases and controls compared with the expected assay variability using a sign test, and compared changes among cases with controls using the Wilcoxon rank-sum test.. Baseline characteristics were similar between cases and controls: median age 45 versus 46 years, 80% versus 81% male, 64% versus 63% non-Hispanic White and median CD4(+) T-cell count 538 versus 601 cells/mm(3), respectively. Mean exposure times were 65 and 15 weeks for abacavir and tenofovir, respectively. We observed no significant changes in biomarkers from the unexposed to exposed state among cases or controls compared with the expected assay variability. We found that no biomarkers were significantly increased among cases compared with controls; however, prothrombin fragment F(1+2) was significantly lower among controls (P=0.035).. In virologically suppressed contemporary HIV-infected patients, abacavir exposure was not associated with increases in biomarkers associated with increased cardiovascular risk.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Risk Factors; Tenofovir

Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation.

Topics: Adenine; Algorithms; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Genomics; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Least-Squares Analysis; Mutation; Nucleosides; Organophosphonates; Phenotype; Reverse Transcriptase Inhibitors; Tenofovir; Thymidine; Zidovudine

The antiretroviral agent abacavir can cause hypersensitivity reaction (HSR) and the presence of HLA-B*57:01 is predictive of abacavir-HSR in Caucasian HIV-infected patients. However, abacavir-HSR also occurs in HLA-B*57:01 negative patients. In these patients, a safe diagnostic tool to dissect clinically suspected HSR against abacavir from adverse reactions against co-administered drugs is mandatory, and abacavir-ELISpot was evaluated. Peripheral blood mononuclear cells from 87 HIV patients were stimulated by abacavir and the production of interferon-γ to the ELISpot was determined. Abacavir treated patients with HSR [confirmed (n=5) or suspected (n=12)] vs without HSR (n=42) displayed significantly higher numbers of abacavir-specific cells (82.3±23.0 or 10.5±4.5 vs -0.5±1.0 spot forming cells per million PBMC, p < .005 each). In conclusion, we established the first abacavir-specific ELISpot. According to our preliminary data, a negative abacavir-ELISpot nearly excludes HSR against abacavir. Thereby the ELISpot may facilitate the decision to continue or withdraw abacavir treatment.

Topics: Adult; Aged; Anti-HIV Agents; Canada; Dideoxynucleosides; Drug Hypersensitivity; Enzyme-Linked Immunospot Assay; Female; HIV Infections; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Young Adult

Abacavir has been associated with myocardial infarction in several studies. This may be related to inflammation and endothelial cell activation. We compared changes in inflammation and endothelial activation markers between antiretroviral-naive adults initiating zidovudine, lamivudine, abacavir, and nonnucleoside reverse transcriptase inhibitor (NNRTI) or this regimen without abacavir. Changes in soluble tumor necrosis factor receptors-I, -II (sTNFR-I, -II), high sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1 (sVCAM-1) from baseline (pre-ART) to a second time point about 24 weeks after initiating antiretroviral therapy (ART) were compared between groups using multivariable linear regression. A total of 37 met eligibility criteria; 12 received abacavir. The median (interquartile range) age was 37 years (27-45). Most were men (32/37), African-American (15/37), or white (15/37). The median nadir CD4(+) and baseline HIV-1 RNA were 230 cells/mm(3) (180-301) and 82,642 copies/ml (34,400-204,703). In all, 15/30 smoked, 7/37 had hypertension, 1/37 had diabetes, and 1/37 had hyperlipidemia. None had coronary or renal disease. Changes in CD4(+) and HIV-1 RNA level and timing of stored samples with regard to ART initiation were not different between groups. In univariable analysis, log transformed percent change in sTNFR-I (p=0.05) and -II (p=0.04) showed significant between-group differences and trended toward significance for sVCAM-1 (p=0.08). These markers decreased less in the abacavir group. After adjustment for confounders, significantly less decrease for sTNFR-II and sVCAM-1 was seen for those receiving the abacavir-containing regimen. When taken with an NNRTI, abacavir induced a smaller decrease in inflammation biomarkers in this cohort, suggesting a possible proinflammatory effect of this nucleoside analogue.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Dideoxynucleosides; Endothelial Cells; Female; HIV Infections; Humans; Inflammation; Male; Middle Aged; Retrospective Studies

Data are sparse on long-term renal toxicity of tenofovir as measured by estimated glomerular filtration rate (eGFR) and progression to advanced stages of chronic kidney disease (CKD). The objective of the study is to determine the incidence of renal impairment associated with the use of tenofovir in HIV-infected patients, using abacavir as a control. In a single tertiary care center, all HIV-infected patients with baseline CKD stage 0 or 1 (CKD-1), who were started on either tenofovir or abacavir from 1998 to 2008 and had at least 1 follow-up eGFR measure on therapy, were included in this retrospective analysis. Progression to CKD stages 2 to 5 was compared using Kaplan-Meier analysis. Progression to CKD-2 and CKD-3 occurred more frequently in patients who received tenofovir than those receiving abacavir (CKD-2, 2-year actuarial frequency, 48.8% vs 23.7%; P < .001, log rank; CKD-3, 5.8% vs 0.0%; P = .028). Only 1 patient in the tenofovir group progressed to CKD-4 and none to CKD-5. Treatment with tenofovir was the only independent factor associated with progression to CKD-2 (hazard ratio [HR], 2.12; 95% confidence interval [CI]: 1.41-3.18; P < .001) and to CKD-3 (HR, 4.91; 95% CI, 1.02-23.7; P = .048). In HIV-infected patients, long-term therapy with tenofovir is associated with mild-to-moderate nephrotoxicity which is significantly higher than in abacavir-treated patients.

Topics: Adenine; Adult; Anti-HIV Agents; Dideoxynucleosides; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; HIV Infections; Hospitals, Veterans; Humans; Incidence; Kidney; Male; Middle Aged; New York City; Organophosphonates; Outpatient Clinics, Hospital; Pilot Projects; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir

Topics: Anti-HIV Agents; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Dideoxynucleosides; Fibrin Fibrinogen Degradation Products; HIV Infections; HIV-1; Humans; Interleukin-6; Longitudinal Studies; Risk Factors; Time Factors; Vascular Cell Adhesion Molecule-1

The potentially life-threatening adverse reactions to Abavacir (ABC), a nucleoside analog reverse transcriptase inhibitor for the treatment of HIV infection, have been known for several years to be limited to individuals expressing the HLA-B57:01 gene. Why the ABC hypersensitivity syndrome is only seen in HLA-B57:01-expressing subjects and what the precise mechanisms underlying this intolerance are remain however controversial. A series of recent studies, particularly a study by Illing et al. recently published in Nature, now answer some of these questions and offer new opportunities to better understand autoimmune disorders and prevent adverse reactions to other drugs.

Topics: Alleles; Anti-HIV Agents; Autoimmunity; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Syndrome

Despite positive developments with the use of combination antiretroviral therapy, a major impediment to limiting the neurocognitive effects of HIV and eradicating HIV brain reservoirs is the penetration of these therapies across the blood-brain barrier (BBB). The focus of our work, therefore, has been to develop tools to significantly improve the penetration of antiretroviral agents to sites of HIV reservoirs, with an emphasis on the CNS. To this end, we have developed an innovative chemical approach--dimeric prodrugs of the antiretroviral agents themselves with a traceless tether. These dimeric prodrugs were designed to serve two purposes: inhibition of P-gp, the major drug efflux protein at the BBB, by occupying two substrate binding sites in the transporter; and prodrug dimers that gain entry into the endothelial cells at the BBB would revert to their monomeric forms in the reducing environment of the cytosol due to breakdown of the traceless tether, thus delivering the therapy. We have demonstrated the feasibility of this design by dimerizing the P-gp substrate and antiviral agent abacavir with a traceless tether. Abacavir dimers displayed potent inhibition of P-gp in two different cellular settings and reverted to active abacavir in the reducing environment of HIV-infected T cells, also leading to antiviral activity. Overall, these experiments point to the excellent promise for future use of dimeric prodrug inhibitors of P-gp for brain penetration of a wide range of CNS-active agents that are substrates of P-gp.

Topics: Animals; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Brain; Capillary Permeability; Chemistry, Pharmaceutical; Dideoxynucleosides; Drug Carriers; Drug Compounding; Drug Design; HIV Infections; Humans; Oxidation-Reduction; Prodrugs; T-Lymphocytes; Technology, Pharmaceutical

In genetics, it is often of interest to discover single nucleotide polymorphisms (SNPs) that are directly related to a disease, rather than just being associated with it. Few methods exist, however, for addressing this so-called "true sparsity recovery" issue. In a thorough simulation study, we show that for moderate or low correlation between predictors, lasso-based methods perform well at true sparsity recovery, despite not being specifically designed for this purpose. For large correlations, however, more specialized methods are needed. Stability selection and direct effect testing perform well in all situations, including when the correlation is large.

Topics: Algorithms; Anti-HIV Agents; Bayes Theorem; Cluster Analysis; Computer Simulation; Dideoxynucleosides; Genetic Association Studies; HIV Infections; Humans; Models, Genetic; Polymorphism, Single Nucleotide

We describe five patients with HIV-2 infection (four antiretroviral-experienced and one antiretroviral-naive) treated with a regimen containing raltegravir. All responded to treatment as demonstrated by viral load and CD4(+) T-cell count monitoring. Our series confirms the clinical effectiveness of raltegravir in HIV-2-infected patients when given with other antiretrovirals to which the virus is susceptible.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Evidence-Based Medicine; Female; HIV Infections; HIV-2; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

To report about a case of acute renal failure due to absence of communication between physician and patient.. A 78 year old man with human immunodeficiency virus (HIV) accessed our hospital and was brought to our attention in August 2011 for severe renal failure. Clinical history revealed that he had been taking highly active antiretroviral therapy with lamivudine/abacavir and fosamprenavir since 2006. In April 2011 due to an augmentation in creatinine plasma levels, a reduction in lamivudine dosage to 100 mg/day and the prescription of abacavir 300 mg/day became necessary. Unfortunately, the patient took both lamivudine and abacavir therefore the association of the two medications (lamivudine/abacavir) lead to asthenia and acute renal failure within a few days.. This case emphasizes the importance about how physicians must pay very careful attention during drug prescription, most particularly, as far as elderly patients are concerned. In fact, communication improvement between physicians and patients can prevent increase of adverse drug reactions related to drug dispensing, with consequential reduction of costs in the healthcare system.

Topics: Acute Kidney Injury; Aged; Antiretroviral Therapy, Highly Active; Asthenia; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Male; Medication Errors

Topics: Administration, Inhalation; Adult; Amyl Nitrite; Anemia, Hemolytic; Anti-HIV Agents; Diagnosis, Differential; Dideoxynucleosides; HIV Infections; Humans; Illicit Drugs; Inhalant Abuse; Iraq; Lamivudine; Male; Travel; Zidovudine

The availability of high-resolution genetic profiling raises the possibility, during the course of a drug development program, of discovering a subset of patients at particular risk of an adverse drug reaction who might be excluded from subsequent randomization into studies and identified as unsuitable for post-licensing use. Such methods depend on the estimation of the risk of adverse drug reactions for patients with differing genetic profiles followed by an assessment of the risks and benefits of their exposure to the drug. In this paper we explore the performance of a number alternative statistical methods for the estimation of risk in terms of the success of the subsequent exclusion rules. The approaches were evaluated using a single-nucleotide polymorphism dataset concerning HIV patients at risk of hypersensitivity to the drug abacavir. Overall we found that a method based on LASSO performed better than the alternatives that we studied, which included a decision-theoretic Bayesian approach, and that its performance suggested suitability for its prospective implementation.

Topics: Anti-HIV Agents; Bayes Theorem; Clinical Trials as Topic; Dideoxynucleosides; Drug Design; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Gene Expression Profiling; Genome, Human; HIV Infections; Humans; Models, Statistical; Polymorphism, Single Nucleotide; Reproducibility of Results; Risk Assessment

Topics: Anti-HIV Agents; Child; Controlled Clinical Trials as Topic; Dideoxynucleosides; Drug Approval; Drug Labeling; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Infant, Newborn; Male; Nitriles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Uric Acid; Urinary Calculi; Urolithiasis

Abacavir use has been associated with cardiovascular risk, but it is unknown whether this association may be partly explained by patients with kidney disease being preferentially treated with abacavir to avoid tenofovir. Our objective was to compare associations of abacavir and tenofovir with cardiovascular risks in HIV-infected veterans.. Cohort study of 10 931 HIV-infected patients initiating antiretroviral therapy in the Veterans Health Administration from 1997 to 2007, using proportional hazards survival regression.. Primary predictors were exposure to abacavir or tenofovir within the past 6 months, compared with no exposure to these drugs, respectively. Outcomes were time to first atherosclerotic cardiovascular event, defined as coronary, cerebrovascular, or peripheral arterial disease; and time to incident heart failure.. Over 60 588 person-years of observation, there were 501 cardiovascular and 194 heart failure events. Age-standardized event rates among abacavir and tenofovir users were 12.5 versus 8.2 per 1000 person-years for cardiovascular disease, and 3.9 and 3.7 per 1000 person-years for heart failure, respectively. In multivariate-adjusted models, including time-updated measurements of kidney function, recent abacavir use was significantly associated with incident cardiovascular disease [hazard ratio 1.48, 95% confidence interval (CI) 1.08-2.04]; the association was similar but nonsignificant for heart failure (1.45, 0.85-2.47). In contrast, recent tenofovir use was significantly associated with heart failure (1.82, 1.02-3.24), but not with cardiovascular events (0.78, 0.52-1.16).. Recent abacavir exposure was independently associated with increased risk for cardiovascular events. We also observed an association between recent tenofovir exposure and heart failure, which needs to be confirmed in future studies.

Topics: Adenine; Anti-Retroviral Agents; Biomarkers, Pharmacological; Cardiovascular Diseases; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Risk Factors; Tenofovir; United States; Veterans; Viral Load

International HIV treatment guidelines recommend HLA-B*57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B*57:01 detection has been developed in the present study.. Two sets of sequence-specific primers were designed, and amplification rapidly detected by real-time PCR.. A total of 108 samples were analyzed in a single-blind fashion, and 41 samples were identified as positive. Complete agreement, with κ = 1 (standard error = 0.0962, p < 0.0001), was found, with a validated methodology used in the EPI109367 clinical trial funded by GlaxoSmithKline, and consisting of low-resolution sequence-specific oligonucleotide PCR, followed by high-resolution sequence-specific oligonucleotide PCR carried out on the HLA-B*57-positive samples.. We provided a detailed characterization of a novel HLA-B*57:01 screening test, which can be easily implemented by those laboratories already involved in the detection of viral load and virus genotyping. Original submitted 26 October 2010; Revision submitted 13 December 2010.

Topics: Anti-HIV Agents; Base Sequence; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Molecular Sequence Data; Pharmacogenetics; Polymerase Chain Reaction

Topics: Dideoxynucleosides; Drug Approval; HIV Infections; Reverse Transcriptase Inhibitors; Tablets; United States; United States Food and Drug Administration

Topics: Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Some studies have suggested that exposure to antiretroviral therapy (ART) with abacavir is associated with an increased risk of acute myocardial infarction (AMI).. Using the Veterans Health Administration's Clinical Case Registry we calculated the risk of AMI and cerebrovascular events (CVA) associated with the cumulative use of abacavir and other nucleoside combinations. We also evaluated the impact of pre-existing chronic kidney disease on the selection of abacavir versus tenofovir in the last recorded ART regimen, and on highly active antiretroviral therapy-associated AMI and CVA risks.. A total of 19,424 human immunodeficiency virus-infected patients contributed 76,376 patient-years of follow. After adjusting for age, hypercholesterolemia, hypertension, type 2 diabetes, and smoking, the hazard ratio (HR) for each year of abacavir use was 1.18 (95% confidence interval [CI], .92-1.50; P=.191) for AMI and 1.16 (95% CI, .98-1.37; P=.096) for CVA. Abacavir use was more common among patients with prior chronic kidney disease than was tenofovir use (12.46% versus 7.15%; P=.0001), and chronic kidney disease was associated with a significantly higher risk of AMI (HR, 2.41; 95% CI, 1.73-3.36), and CVA (HR, 1.80; 95% CI, 1.44-2.24). Compared with patients who received neither tenofovir nor abacavir, patients who received tenofovir had lower risk of AMI (HR, 0.16; 95% CI, .08-.33; P=.0001) and CVA (HR, 0.22; 95% CI, .15-.32; P=.001). Use of abacavir was associated with lower risk of CVA (HR, 0.60; 95% CI, .45-.79).. We observed no association between cumulative or current abacavir use and AMI or CVA. Abacavir use was more common than was tenofovir use among patients with prior chronic kidney disease, and chronic kidney disease independently predicted higher rates of AMI and CVA.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV Infections; Humans; Ischemic Attack, Transient; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Organophosphonates; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Stroke; Tenofovir; United States; United States Department of Veterans Affairs

Topics: Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Myocardial Infarction; Stroke

The presence of autonomic dysfunction in HIV patients is largely unknown. Early studies found autonomic dysfunction in patients with AIDS. Antiretroviral combination therapy (ART) has dramatically changed the course of the disease and improved prognosis and decreased morbidity.. To evaluate whether autonomic dysfunction is present in an ART treated HIV population and if so to identify factors of importance.. HIV patients receiving ART for at least 12 months (n = 97) and an age-matched control group of healthy volunteers (n = 52) were included. All were non-diabetic and had never received medication for hypertension. Following a 10 min resting period a 15 min ECG recording was performed. Heart-rate variability (HRV) analysis was performed in accordance with current guidelines and data reported as mean [interquartile range].. Mean normal-to-normal (NN) and total HRV measured as standard deviation of normal-to-normal (SDNN) was lower in HIV patients compared to controls (905 vs. 982 ms; p<0.001 and 48 vs. 54 ms; p = 0.028, respectively). No differences were found between the groups in parasympathetic activity measured as square root of the mean squared difference of successive NN-intervals (RMSSD) or the percent of differences between adjacent NN intervals greater than 50 ms (pNN50). In the HIV positives, haemoglobin A1c correlated inversely with SDNN, RMSSD and pNN50 (p<0.05). Total cholesterol and LDL-C correlated inversely with RMSSD and pNN50 (p<0.05). Neither HIV duration, HIV-RNA, CD4 cell count nor CD4 nadir correlated with time or phase domain HRV variables.. Moderate autonomic dysfunction is present in HIV positives patients even with suppressed viral load due to ART. The dysfunction is correlated with HbA1c and hypercholesterolemia but not to duration of HIV or whether the patients were receiving protease inhibitors as part of the ART regime.

Topics: Anti-HIV Agents; Blood Glucose; Cholesterol; Dideoxynucleosides; Glycated Hemoglobin; Heart Rate; HIV Infections; Humans

Increasing the safety in Immunogenetics Labs, in the era of antiretroviral pharmacogenomics, represents an imperative goal. To this purpose, we tested saliva and buccal cells as biological sources of DNA, alternative to peripheral blood, for HLA-B*57:01 genomic typing of HIV positive patients eligible to treatment with abacavir.. Blood, saliva and buccal cells of 20 voluntary donors and 20 HIV positive patients were collected. DNA was extracted with a manual commercial kit and an automated platform. Quality and quantity of DNA was evaluated with different procedures. The suitability and reliability of DNAs for HLA-B*57:01 genotyping was checked at low and high resolution level, using PCR-SSP (sequence specific primers PCR), revPCR-SSO (reverse sequence specific oligonucleotides PCR), bead array and SBT (sequence based typing) techniques.. DNA concentrations were qualitatively very good and quantitatively comparable in all the specimens tested with an inferior yield for cotton swabs. Comparing the results of HLA typing with different methodologies, the 100% of reproducibility was achieved.. The viral load of buccal epithelial cells or saliva is extremely low. Here we demonstrated that the DNA from these alternative sources is appropriate for HLA-B*57:01 typing. We strongly recommend the use of this procedure to increase the safety in the lab when dealing with infectious samples.

Topics: Dideoxynucleosides; DNA; Genotype; HIV Infections; HLA-B Antigens; Humans; Polymerase Chain Reaction; Saliva

Limited data are available on the use of unboosted atazanavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-experienced HIV-infected patients.. We conducted a multicentre, retrospective study among patients with plasma HIV-1 RNA levels <50 copies/mL under antiretroviral therapy who switched to unboosted atazanavir + NRTIs between January 2002 and December 2008. Virological failure during follow-up was defined as a confirmed plasma HIV-1 RNA level >50 copies/mL. Baseline risk factors for virological failure were identified using Cox proportional hazards models.. A total of 886 patients were analysed. At baseline, median age was 44 years, 71.5% were males and median CD4 cell count was 490 cells/mm(3). NRTIs used in combination with atazanavir were tenofovir, abacavir and emtricitabine/lamivudine in 36.9%, 44.1% and 94.4% of patients, respectively. Median follow-up was 21 months. The 3 year probability of virological failure was 20.1%. Only a history of virological failure under NRTIs [hazard ratio (HR) 1.63, P = 0.049] and under protease inhibitors (HR 2.04, P = 0.006) were significantly associated with the risk of virological failure. Among the 431 patients without a prior history of virological failure, the 3 year probability of virological failure was 11.3%, and only hepatitis C virus co-infection (HR 2.25, P = 0.026) and abacavir use (HR 0.43, P = 0.04) were associated with the risk of virological failure. Safety of the switch was satisfactory, with improvement of the lipid profile.. In patients with virological suppression and no prior history of virological failure, a switch to unboosted atazanavir in combination with NRTIs is associated with a low probability of virological failure and a good safety profile.

Topics: Adenine; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4 Lymphocyte Count; Cohort Studies; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Organophosphonates; Pyridines; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Viral Load

Topics: Adenine; Adult; Anti-HIV Agents; Case-Control Studies; Chemokine CCL2; Dideoxynucleosides; Endothelium, Vascular; Female; HIV Infections; HIV-1; Humans; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Vascular Cell Adhesion Molecule-1; Vasodilation

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Developing Countries; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Health Planning; Health Services; HIV Infections; Humans; Lamivudine; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Young Adult

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Organophosphonates; Tenofovir

Current or recent use of abacavir for treating human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased rates of myocardial infarction (MI). Given the role of platelet aggregation in thrombus formation in MI and the reversible nature of the abacavir association, we hypothesized that patients treated with abacavir would have increased platelet reactivity.. In a prospective study in adult HIV-infected patients, we determined associations between antiretrovirals (ARVs), and in particular the nucleoside reverse transcriptase inhibitor abacavir, and platelet reactivity by measuring time-dependent platelet aggregation in response to agonists: adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), collagen, and epinephrine.. Of 120 subjects, 40 were ARV-naive and 80 ARV-treated, 40 of whom were receiving abacavir. No consistent differences in platelet reactivity were observed between the ARV-naive and ARV-treated groups. In contrast, within the ARV-treated group, abacavir-treated subjects had consistently higher percentages of platelet aggregation upon exposure to ADP, collagen, and epinephrine (P = .037, P = .022, and P = .032, respectively) and had platelets that were more sensitive to aggregation upon exposure to TRAP (P = .025).. The consistent increases in platelet reactivity observed in response to a range of agonists provides a plausible underlying mechanism to explain the reversible increased rates of MI observed in abacavir-treated patients.

Topics: Adenosine Diphosphate; Adult; Cohort Studies; Collagen; Cross-Sectional Studies; Dideoxynucleosides; Drug Interactions; Epinephrine; Female; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Platelet Aggregation; Prospective Studies; Reverse Transcriptase Inhibitors; Statistics, Nonparametric

HIV and type 2 diabetes are known risk factors for albuminuria, but no previous reports have characterized albuminuria in HIV-infected patients with diabetes.. We performed a cross-sectional study including 73 HIV-infected adults with type 2 diabetes, 82 HIV-infected non-diabetics, and 61 diabetic control subjects without HIV. Serum creatinine >1.5 mg/dL was exclusionary. Albuminuria was defined as urinary albumin/creatinine ratio >30 mg/g.. The prevalence of albuminuria was significantly increased among HIV-infected diabetics (34% vs. 13% of HIV non-diabetic vs. 16% diabetic control, p = 0.005). HIV status and diabetes remained significant predictors of albuminuria after adjusting for age, race, BMI, and blood pressure. Albumin/creatinine ratio correlated significantly with HIV viral load (r = 0.28, p = 0.0005) and HIV-infected subjects with albuminuria had significantly greater cumulative exposure to abacavir (p = 0.01). In an adjusted multivariate regression analysis of HIV-infected subjects, the diagnosis of diabetes (p = 0.003), higher HIV viral load (p = 0.03) and cumulative exposure to abacavir (p = 0.0009) were significant independent predictors of albuminuria.. HIV and diabetes appear to have additive effects on albuminuria which is also independently associated with increased exposure to abacavir and HIV viral load. Future research on the persistence, progression and management of albuminuria in this unique at-risk population is needed.

Topics: Adult; Albuminuria; Anti-HIV Agents; Blood Pressure; Body Mass Index; CD4-Positive T-Lymphocytes; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dideoxynucleosides; Female; Glomerular Filtration Rate; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; Humans; Male

It is unknown whether systemic endothelial dysfunction underlies the association between nephropathy and cardiovascular disease (CVD) in persons infected with human immunodeficiency virus (HIV). Spot urine protein to creatinine ratio, spot urine albumin to creatinine ratio, creatinine clearance, estimated glomerular filtration rate, and flow-mediated dilation (FMD) of the brachial artery were evaluated in 123 study participants infected with HIV (58 receiving antiretroviral therapy [ART] and 65 not receiving ART) with no history of diabetes or hypertension. None of the renal markers, modeled as either continuous or categorical variables, correlated with FMD. Contrary to expectations, endothelial dysfunction may not be the link between nephropathy and CVD in HIV.

Topics: Adenine; Adult; Albuminuria; Alkynes; Anti-HIV Agents; Benzoxazines; Brachial Artery; Chi-Square Distribution; Creatinine; Cyclopropanes; Dideoxynucleosides; Endothelium, Vascular; Female; Glomerular Filtration Rate; HIV Infections; Humans; Linear Models; Male; Middle Aged; Organophosphonates; Proteinuria; Tenofovir; Ultrasonography; Vasodilation

The HLA-B*57:01 allele is associated with a hypersensitivity reaction to abacavir, and its prevalence varies in different populations. The aim of the study was to investigate HLA-B*57:01 prevalence in the Czech HIV-infected population. HLA-B*57:01 prevalence in our cohort was 5.33%, which is similar to the situation in other Central European countries.

Topics: Anti-HIV Agents; Cross-Sectional Studies; Czech Republic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Prevalence

The use of abacavir and didanosine in HAART has been associated with an increased risk of myocardial infarction in HIV-infected patients. The aim of this study was to address the development of endothelial dysfunction in cultivated coronary artery endothelial cells (HCAECs) in response to abacavir, didanosine and tenofovir. We examined the impact of these drugs on the expression levels of the proinflammatory, oxidative stress and apoptosis regulating genes in HCAECs.. We tested gene and protein expression changes in HCAECs in response to abacavir, didanosine and tenofovir using quantitative real-time reverse transciptase PCR, FACS and ELISA. The assessed genes/proteins included the proinflammatory molecules VCAM-1, ICAM-1, MCP-1, RANTES and IL-6. In addition, we assessed the gene expression of the intracellular reactive oxygen producing NADPH oxidase subunit gp91(PHOX) and the apoptosis regulating molecules Bcl-2 and BAD.. Exposure of HCAECs to abacavir, didanosine and tenofovir resulted in no statistically significant changes in any of the tested genes/proteins at any time point or at any concentration.. We found no evidence that abacavir, didanosine or tenofovir had direct in vitro effects on coronary endothelial cell gene transcription and protein expression of the selected mediators. If abacavir or didanosine increase cardiovascular risk, it is likely not through the direct endothelial activation pathways tested in these experiments. However, further studies are needed to completely exclude the toxicity of abacavir or didanosine on endothelial cells.

Topics: Adenine; Anti-HIV Agents; Apoptosis; Cardiovascular Diseases; Cell Adhesion Molecules; Coronary Vessels; Cytokines; Didanosine; Dideoxynucleosides; Endothelial Cells; Gene Expression; Gene Expression Profiling; HIV Infections; HIV-1; Humans; Inflammation; NADPH Oxidases; Organophosphonates; Oxidative Stress; Primary Cell Culture; Proto-Oncogene Proteins; Tenofovir

CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.

Topics: Adenine; Anti-HIV Agents; Cell Survival; Cells, Cultured; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Macrophages; Nucleosides; Nucleotides; Organophosphonates; Tenofovir

The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI).. This was a prospective nationwide cohort study which included all Danish HIV-infected patients on highly active antiretroviral therapy (HAART) from 1995 to 2005 (N = 2952). Data on hospitalization for MI and comorbidity were obtained from Danish medical databases. Hospitalization rates for MI after HAART initiation were calculated for patients who used abacavir and those who did not. We used Cox's regression to compute incidence rate ratios (IRR) as a measure of relative risk for MI, while controlling for potential confounders (as separate variables and via propensity score) including comorbidity.. Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers.. Hospitalization rates for MI were 2.4/1000 person-years (PYR) [95% confidence interval (CI) 1.7-3.4] for abacavir nonusers and 5.7/1000 PYR (95% CI 4.1-7.9) for abacavir users. The risk of MI increased after initiation of abacavir [unadjusted IRR = 2.22 (95% CI 1.31-3.76); IRR adjusted for confounders = 2.00 (95% CI 1.10-3.64); IRR adjusted for propensity score = 2.00 (95% CI 1.07-3.76)]. This effect was also observed among patients initiating abacavir within 2 years after the start of HAART and among patients who started abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen.. We confirmed the association between abacavir use and increased risk of MI. Further studies are needed to control for potential confounding not measured in research to date.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Comorbidity; Denmark; Dideoxynucleosides; Epidemiologic Methods; Female; HIV Infections; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Proportional Hazards Models; Time Factors

Human leukocyte antigen (HLA)-B(*)5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC) in White and Hispanic subjects. Across the UK, limited data exist on HLA-B(*)5701 prevalence in HIV-1-infected subjects. We determined HLA-B(*)5701 prevalence in the general HIV-1-infected population and in specific ethnic groups, particularly Black Africans who, in general, exhibit greater genetic diversity. We also compared HLA-B(*)5701 results obtained from local laboratories with those from a central provider.. Multi-centre, observational study. All HIV-1-infected adult individuals receiving care at participating centres were eligible, irrespective of treatment status or prior exposure to ABC. Subjects provided samples for HLA-B(*)5701 assessment by both local (blood) and central laboratories (buccal swabs). HLA-B(*)5701 prevalence was adjusted to represent the ethnic group composition of the general UK population, and by main ethnic group. RESULTS; From eight UK centres, 1494 subjects [618 (41%) White, 770 (52%) Black] were recruited. Eighty-nine per cent of Black subjects reported an immediate country of origin in Africa. Overall adjusted HLA-B(*)5701 prevalence was 4.55% [95% confidence interval (CI) 3.49% to 5.60%]. Among White subjects, prevalence was 7.93% (CI 5.80% to 10.06%). Among Black subjects, only two (both Ugandan) were HLA-B(*)5701 positive giving a rate of 0.26% (CI 0.07% to 0.94%).. HLA-B(*)5701 prevalence was similar to previously reported rates in White HIV-infected subjects but considerably lower than that reported in Black HIV-1-infected subjects, as a result of the large proportion of Black African subjects.

Topics: Adult; Africa; Aged; Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; Epidemiologic Studies; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Prospective Studies; United Kingdom; White People; Young Adult

We present a case of relapsing cryptococcal meningitis unresponsive to standard therapy. Voriconazole induction, including the utilization of voriconazole therapeutic drug monitoring in both serum and CSF, with transition to voriconazole plus interferon-gamma (IFN-gamma) was successfully used in a patient receiving antiretroviral therapy with abacavir/lamivudine and lopinavir/ritonavir. Initial voriconazole levels at standard doses of 4 mg/kg twice daily intravenously were low when co-administered with lopinavir/ritonavir but increased to recommended therapeutic levels with an increase of the voriconazole dose to 7 mg/kg twice daily. This case highlights the utility of voriconazole therapeutic drug monitoring when prescribed concurrently with a ritonavir boosted protease inhibitor and the potential role of combination therapy with IFN-G for refractory cryptococcal meningitis.

Topics: Anti-HIV Agents; Antifungal Agents; Cerebrospinal Fluid; Dideoxynucleosides; Drug Monitoring; HIV Infections; Humans; Interferon-gamma; Lamivudine; Male; Meningitis, Cryptococcal; Pyrimidines; Ritonavir; Serum; Triazoles; Voriconazole; Young Adult

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination antiretroviral therapy in HIV-infected patients. It is currently recommended as a preferred or an alternative NRTI in antiretroviral-naïve patients. The major toxicity of abacavir is a hypersensitivity reaction (HSR), which occurs in approximately 5% of treated patients. There is a strong association between the human leukocyte antigen (HLA)-B*5701 allele and abacavir HSR, which has allowed for rapid acceptance of genetic screening for HLA-B*5701 in clinical use. Canadian clinicians working in hospital centers with HLA typing capacity opted to launch a pilot project in 2006 to offer the screening test as standard of care to HIV-infected patients. Currently, more than 11,000 HLA-B*5701 tests have been performed, among which 6.3% are positive. Continued efforts have been made to ensure that testing is available to all HIV-infected patients to widen the patients' therapeutic options. HLA-B*5701 screening shows clinical use and preliminary data suggest cost-effectiveness.

Topics: Alleles; Anti-HIV Agents; Canada; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir.. NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years.. The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg).. We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension.

Topics: Adult; Age Factors; Aged; Blood Pressure; Cholesterol, HDL; Diabetes Mellitus; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Male; Middle Aged; Models, Statistical; Myocardial Infarction; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Risk; Smoking; Uncertainty

Topics: Adult; Blood Specimen Collection; Clinical Laboratory Techniques; Deoxyguanine Nucleotides; Dideoxynucleosides; HIV Infections; Humans; Intracellular Fluid; Leukocytes, Mononuclear; Male; Middle Aged; Reproducibility of Results

The selection of drug-resistant variants of human immunodeficiency virus type 1 (HIV-1) is an impediment to the efficiency of antiretroviral (ARV) therapy. We have developed an allele-specific real-time PCR assay to explore the presence of K65R minority species among treated HIV-1 subtype B and C infections. Thirty HIV-1 subtype C- and 26 subtype B-infected patients lacking K65R as determined by conventional sequencing methods were studied, and viral minority species were found in four HIV-1 subtype C samples.

Topics: Alkynes; Alleles; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Nevirapine; Polymerase Chain Reaction; Zidovudine

Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence.. We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008.. The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56).. Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Oligopeptides; Organophosphonates; Proportional Hazards Models; Prospective Studies; Pyridines; Pyrimidinones; Risk Factors; Switzerland; Tenofovir; Zidovudine

Prospective pharmacogenetic screening for the human leucocyte antigen (HLA) B*5701 allele can significantly reduce the number of cases of abacavir-related hypersensitivity among HIV-infected patients treated with this drug. The aim of this study was to establish the frequency of the HLA B*5701 variant in HIV-infected Poles.. The sequence-specific primer (SSP) test was used to assess the feasibility of the introduction of such testing in clinical practice. For this purpose, 234 randomly selected HIV-positive patients were screened using a low-resolution SSP assay, with HLA B*5701-positive results confirmed using a high-resolution test.. The HLA B*5701 variant was found in 11 of 234 subjects (4.7%). Testing with the selected method proved quick and reliable.

Topics: Adult; Alleles; Dideoxynucleosides; Drug Hypersensitivity; Feasibility Studies; Female; Gene Frequency; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Mutation; Poland; Polymerase Chain Reaction; Predictive Value of Tests; Reverse Transcriptase Inhibitors; Skin Tests

It remains unclear if certain antiretroviral medications, particularly abacavir, compromise response to HCV therapy. Such data could inform the selection of appropriate antiretrovirals in HIV/HCV-coinfected patients. The aim of this study was to determine if use of abacavir, as well as other antiretrovirals, was associated with reduced response to pegylated interferon (PEG-IFN) plus ribavirin.. A cohort study was performed among antiretroviral-treated HIV/HCV-coinfected patients initiating PEG-IFN plus ribavirin between January 2001 and June 2007 at six sites in the United States. Abacavir and other antiretrovirals represented exposures of interest. Study outcomes included an early virological response (> or =2 log IU/ml decrease in HCV viral load at 12 weeks) and sustained virological response (undetectable HCV viral load 24 weeks after treatment discontinuation).. Among 212 patients, 74 (35%) received abacavir. For patients infected with HCV genotype 1 or 4, no differences were observed between abacavir users and non-users in early virological response (26 [40%] versus 53 [44%]; adjusted odds ratio [OR] 1.00; 95% confidence interval [CI] 0.50-2.00) or sustained virological response (8 [13%] versus 13 [12%]; adjusted OR 1.34; 95% CI 0.50-3.62). Among genotype 2 and 3 patients, rates of early virological response (7 [78%] versus 16 [89%]; OR 0.44; 95% CI 0.05-3.76) and sustained virological response (3 [33%] versus 8 [44%]; OR 0.63; 95% CI 0.12-3.32) were also similar between abacavir users and non-users. No association was found between other antiretrovirals and a lack of early or sustained response.. Use of abacavir or other antiretroviral medications was not associated with reduced early or sustained virological response rates.

Topics: Adult; Antiviral Agents; Cohort Studies; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Ribavirin; Treatment Outcome; Viral Load

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Male; Reverse Transcriptase Inhibitors; Taiwan

Efficacy and tolerability of nevirapine-based HAART regimens were retrospectively evaluated. HIV-1-infected patients were included if they had been receiving a NVP-containing HAART regimen for at least 60 months, regardless of the reason for its initiation. A total of 82 patients were included in this study. The median follow-up time period was 96 months (range 64-120). At the time of starting NVP-based therapy, 31.7% (26 patients) were antiretroviral-naive, while 68.3% (56 patients) switched to an NVP-based strategy because of intolerance to the prior regimen, failure of a previous regimen or for simplification purposes. Coinfection with hepatitis B or C viruses was present in 26.8% of the patients (n 22). The most frequent nucleoside analogue backbone was zidovudine/lamivudine (52.4%) followed by stavudine/lamivudine (15.8%). A protease inhibitor was concomitantly administered in 2.4% of cases. To investigate the tolerability, we report the results separately on the basis of the presence/absence of HBV and/or HCV coinfection. Coinfected patients displayed significantly higher baseline liver enzymes than non-coinfected patients. Nevertheless, ALT levels showed a constant decrease over time in coinfected patients. Overall, median triglycerides, HDL and total cholesterol values tended to be lower in coinfected patients than in the remaining subjects. In particular, there was a significant decrease in triglyceride values in both groups and, concomitantly, a slight increase in total cholesterol. On the other hand, HDL cholesterol demonstrated a progressive increase. Finally, no change was found in glucose plasma levels, which always remained within normal ranges. In conclusion, no long-term toxicities associated with the use of nevirapine beyond five years were documented in our cohort of patients, even in coinfected patients. Long-term exposure to nevirapine was associated with optimal HIV suppression and favourable lipidic and glucidic profiles.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Comorbidity; Dideoxynucleosides; Female; Hepatitis, Viral, Human; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lipids; Liver Function Tests; Male; Middle Aged; Nevirapine; Retrospective Studies; Stavudine; Viral Load; Young Adult; Zidovudine

Topics: Adenine; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Lamivudine; Multicenter Studies as Topic; Oligopeptides; Organophosphonates; Pyridines; Randomized Controlled Trials as Topic; Tenofovir

To study the correlation between the HLA-B*5701 allele and the single nucleotide polymorphism in HCP5 (rs2395029).. All HIV patients naive for abacavir seen at our institution between September 2007 and December 2008 were prospectively screened for HLA-B*5701. HCP5 rs2395029 genotyping was carried out by allelic discrimination using the TaqMan 5'-nuclease assay. High-resolution HLA class I typing was undertaken using sequence-specific primers.. A total of 245 HIV patients were included in the study. A good correlation between HLA-B*5701 and HCP5 was observed (negative and positive predictive values of 100% and 93%, respectively).. The use of HCP5 rs2395029 testing could be as useful as HLA-B*5701 typing to prevent the abacavir hypersensitivity reaction. Given that HCP5 testing is cheaper, less time-consuming and easier to perform than HLA typing, it may confidently replace the latter in clinical settings.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; Major Histocompatibility Complex; Male; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prospective Studies; RNA, Long Noncoding; RNA, Untranslated

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Capsules; Cyclopropanes; Dideoxynucleosides; Drug Approval; Drug Labeling; Drugs, Generic; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Tablets; United States; United States Food and Drug Administration; Zidovudine

Abacavir sulfate (abacavir) is associated with a hypersensitivity reaction (HSR) that affects 5-8% of patients. While serious complications are rare, failure to identify it, or abacavir re-challenge following HSR, can be fatal. Genetic screening for HLA-B*5701 can identify patients who are likely to experience an HSR and reduces the incidence of the reaction.. We assessed the intrinsic and practical value, from the US healthcare system perspective, of prospective HLA-B*5701 screening among a population of antiretroviral-naive patients without elevated risk factors for cardiovascular disease, plasma HIV RNA >100,000 copies/mL, or pre-existing renal insufficiency.. Two approaches were used to evaluate the costs and benefits of prospective screening. First, the efficiency of HLA-B*5701 screening compared with no screening prior to abacavir initiation (intrinsic value of screening) was evaluated using a 60-day decision-tree model. Next, the practical value of screening was assessed using a lifetime discrete-event simulation model that compared HLA-B*5701 screening prior to abacavir use versus initiation with a tenofovir-containing regimen. Screening-effectiveness parameters were taken from an open-label trial that incorporated screening prior to abacavir initiation and other published studies. Treatment efficacy was derived from clinical trials. Modelling assumptions, costs ($US, year 2007 values) and other parameters were derived from published sources, primary data analysis and expert opinion. Multiple one-way sensitivity and scenario analyses were performed to assess parameter uncertainty. The primary outcome measure for the short-term screening versus no screening analysis was cost per patient. For the long-term analysis, outcomes were presented as QALYs. Costs and effects were discounted at 3% per year.. Over the first 60 days of treatment, prospective screening prior to abacavir initiation cost an additional $US17 per patient and avoided 537 HSRs per 10,000 patients. The per-patient cost of screening was sensitive to the cost of the genetic test, HSR costs and screening performance. In the lifetime model, screening-informed abacavir use was more effective and less costly than initiation with a tenofovir-containing regimen in the base case and in sensitivity analyses.. Our results suggest that prospective HLA-B*5701 screening prior to abacavir initiation produces cost savings and should become a standard component of HIV care.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Computer Simulation; Cost-Benefit Analysis; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Middle Aged; Models, Economic; Organophosphonates; Quality-Adjusted Life Years; Tenofovir; United States

To assess associations between abacavir (ABC) use and systemic inflammation.. Nested case-control study.. The Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) cohort participants who initiated ABC were matched, using propensity score methods, to ABC-unexposed persons. Levels of high-sensitivity C-reactive protein (hsCRP) (microg/ml), interleukin-6 (IL-6) (pg/ml), and D-dimer (microg/ml) were measured from pre-HAART and on-HAART plasma. Random-effects models compared markers by ABC exposure and by changes from pre-HAART levels.. Biomarkers were measured in N = 508 matched pairs (328 women; 180 men). Pre-HAART levels did not differ by exposure group except that hsCRP levels were higher among WIHS women who subsequently used ABC (P = 0.04). Regardless of ABC use, mean hsCRP increases and D-dimer reductions were seen when comparing pre-HAART to on-HAART levels, in the overall group (28 and -27%), for MACS men (28 and -31%) and for WIHS women [29 and -24%, P < 0.01 for all]; IL-6 levels declined in MACS men (P = 0.02). No adjusted biomarker level differences existed by ABC exposure at the on-HAART visit. HIV RNA reductions correlated with D-dimer (r = 0.14, P < 0.01) and IL-6 (r = 0.12, P < 0.01) reductions. Associations between ABC use and mean biomarker levels were modified by pre-HAART antiretroviral therapy experience. Renal dysfunction was equally likely among non-ABC and ABC recipients.. ABC use was not associated with plasma elevations in hsCRP, IL-6, and D-dimer. Mechanisms other than increased systemic inflammation may account for ABC's reported association with increased cardiovascular disease. HAART-associated reductions in D-dimer and IL-6 were apparent regardless of ABC use and were correlated with HIV RNA reductions.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; C-Reactive Protein; Case-Control Studies; Dideoxynucleosides; Female; Fibrin Fibrinogen Degradation Products; HIV Infections; HIV-1; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral

Abacavir's effect on cardiovascular function has not been studied prospectively. We measured augmentation index (a measure of arterial stiffness) in 20 men who switched from abacavir to tenofovir. After 4 weeks, mean augmentation index reduced from 22% by 4% (P = 0.03) and Framingham risk score by 2% (P = 0.01), which was driven by lower total cholesterol (0.8 mmol/l; P = 0.002). Consistent trends were observed through week 24. Changes in C-reactive protein, interleukin-6 and D-dimer were inconsistent and only occurred from week 12. Abacavir may impair cardiovascular function by increasing total cholesterol levels.

Topics: Adenine; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Assessment; Tenofovir; Vascular Resistance

The role of exposure to specific antiretroviral drugs on risk of myocardial infarction in human immunodeficiency virus (HIV)-infected patients is debated in the literature.. To assess whether we confirmed the association between exposure to abacavir and risk of myocardial infarction (MI) and to estimate the impact of exposure to other nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-NRTIs on risk of MI, we conducted a case-control study nested within the French Hospital Database on HIV. Cases (n = 289) were patients who, between January 2000 and December 2006, had a prospectively recorded first definite or probable MI. Up to 5 controls (n = 884), matched for age, sex, and clinical center, were selected at random with replacement among patients with no history of MI already enrolled in the database when MI was diagnosed in the corresponding case. Conditional logistic regression models were used to adjust for potential confounders.. Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample (odds ratios [ORs], 2.01; 95% confidence interval [CI], 1.11-3.64) but not in the subset of matched cases and controls (81%) who did not use cocaine or intravenous drugs (1.27; 0.64-2.49). Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir (OR, 1.53; 95% CI, 1.21-1.94 per year) and lopinavir with ritonavir (1.33; 1.09-1.61 per year). Exposure to all non-NRTIs was not associated with risk of MI.. The risk of MI was increased by cumulative exposure to all the studied PIs except saquinavir and particularly to amprenavir/fosamprenavir with or without ritonavir and lopinavir with ritonavir, whereas the association with abacavir cannot be considered causal.

Topics: Adult; Anti-HIV Agents; Carbamates; Case-Control Studies; Cohort Studies; Confidence Intervals; Dideoxynucleosides; Female; France; Furans; HIV Infections; Hospitals, Isolation; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Organophosphates; Regression Analysis; Risk; Ritonavir; Sulfonamides

Topics: Adult; Diabetes Mellitus; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Hypoglycemia

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Dideoxynucleosides; HIV Infections; Humans; Pilot Projects; South Africa; Treatment Outcome

To compare plasma antiretroviral concentrations in HIV-HCV co-infected and in matched HIV mono-infected patients.. This was a cross-sectional, observational study. Antiretroviral trough concentrations (C(min)) in plasma were measured in HIV-HCV co-infected patients with liver disease documented by liver biopsy, matched with HIV mono-infected patients according to gender and antiretroviral treatment. C(min) values in serum were measured using an HPLC method. Statistical analysis was performed using the Wilcoxon test.. Seventy-three HIV-HCV co-infected patients and 66 HIV-infected patients were enrolled; 70% of patients were receiving a protease inhibitor (PI)- and 30% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Among the 73 co-infected patients, 27 had a fibrosis score (Fibrotest(®)) of F4. Abacavir was the only nucleoside reverse transcriptase inhibitor whose trough concentrations differed between the co-infected and mono-infected groups. PI median plasma C(min) values were not different in the two groups, except for lopinavir, with a lower C(min) in the co-infected group than in the HIV-infected group (median 3673 versus 5990 ng/mL, P=0.04), and nelfinavir, with significantly higher concentrations in the co-infected group. Seventy-five percent of co-infected patients scoring F4, 33% of those scoring F0-F3 and 12% of HIV-infected patients were underdosed (P=0.02). Co-infected patients receiving an NNRTI had a higher plasma C(min) than HIV-infected patients; median C(min) was 3583 versus 1494 ng/mL (P=0.025) and 5331 versus 3954 ng/mL (P=0.10) for efavirenz and nevirapine, respectively. Overall, there was a greater proportion of co-infected patients with high concentrations of both NNRTIs (15/23) compared with HIV mono-infected patients (5/21) (P=0.008), especially in co-infected patients with an advanced liver fibrosis stage.. Median plasma C(min) values differed significantly between HIV and HIV-HCV co-infected patients for abacavir, lopinavir and efavirenz. NNRTIs were strongly overdosed in HIV-HCV co-infected patients.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Benzoxazines; Case-Control Studies; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclopropanes; Dideoxynucleosides; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney; Lamivudine; Male; Organophosphonates; Sex Factors; Tenofovir

Human immunodeficiency virus (HIV) infection and the receipt of antiretroviral therapy have been associated with the development of cardiovascular disease. The occurrence of cardiovascular events in HIV-infected patients has often been associated with treatment-induced dyslipidemia, insulin resistance, and body composition changes. These treatment-related complications are often the result of exposures to protease inhibitors or thymidine analogs such as stavudine or zidovudine. Recent investigations, however, have suggested an association between exposure to the nucleoside reverse transcriptase inhibitor, abacavir, and the occurrence of cardiovascular disease events. Based on these findings, current guidelines recommend using caution in patients receiving abacavir who are at a high risk for cardiovascular disease. Decisions to replace abacavir in a patient's regimen should be considered on an individual basis and with complete evaluation of the associated benefits and risks. Furthermore, additional studies are necessary to definitively determine the association between abacavir exposure and the occurrence of cardiovascular disease events. Studies are also necessary to definitively identify the contributions of both HIV infection and individual antiretroviral agents on the development of cardiovascular disease.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers, Pharmacological; Cardiovascular Diseases; CD4 Lymphocyte Count; Dideoxynucleosides; HIV; HIV Infections; Humans; Randomized Controlled Trials as Topic; Risk Factors; Viral Load

Abacavir (ABC) is an antiretroviral drug highly effective in the treatment of HIV, but its intake can cause severe hypersensitivity reaction (HSR). A strong association between HLA-B(*)57:01 and ABC HSRs was reported by several studies, which demonstrated that HLA-B(*)57:01 screening had a 100% negative predictive value and that it could accurately identify patients at high risk of ABC HSRs. We propose a new sequence-specific primer PCR assay based on fluorescence detection through CE which is highly sensitive, allowing the use of non-infective sources of DNA such as saliva and buccal swabs, in addition to blood and reproducible, allowing automation of the analytical process. The results of our study were first compared with a standard sequence-specific primer PCR technique and reported a concordance of 100%, and then a blind external validation further confirmed the accuracy of our method.

Topics: Blood Chemical Analysis; Cheek; Dideoxynucleosides; DNA; DNA Primers; Drug Hypersensitivity; Electrophoresis, Capillary; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Mouth Mucosa; Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence

A hypersensitivity reaction to abacavir develops in approximately 2-8% of HIV patients receiving this drug and is strongly associated with presence of the human leukocyte antigen (HLA)-B*5701. Screening for HLA-B*5701 reduces the risk of developing an abacavir hypersensitivity reaction. The carriage rate of HLA-B*5701 has not been studied in Georgia before 2009. Objective of the study was to determine HLA-B*5701 prevalence in HIV-infected patients in Georgia. One hundred and sixty HIV positive patients attending Georgian Infectious Diseases, AIDS and Clinical Immunology Research Center in 2009 were recruited for the study. None of the patients had previously been treated with abacavir. Blood samples were collected and screened for HLA-B*5701 prior to abacavir prescription. Of 160 patients recruited 9 tested HLA B*5701 positive - 5.6% (95% CI: 2.6-10.4%). Of these nine patients 7 were males (male prevalence: 6.5%, 95% CI: 2.6-12.9 %) and 2 females (female prevalence: 4.8%, 95% CI: 0.6-16.2%). The first prospective study of HLA-B*5701 prevalence in Georgia show similar results to the results of other studies. Abacavir still remains one of the key drugs of antiretroviral regimens in Georgia and other countries. Therefore, prospective HLA-B*5701 screening should be implemented in all settings where abacavir is widely used to guide selection of ART regimens and to reduce the risk of potentially life threatening hypersensitivity reaction.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Georgia (Republic); HIV; HIV Infections; HLA-B Antigens; Humans; Male; Prospective Studies; Reverse Transcriptase Inhibitors

Q145M, a mutation in a conserved human immunodeficiency virus type 1 reverse transcriptase (RT) region, was reported to decrease susceptibility to multiple RT inhibitors. We report that Q145M and other Q145 mutations do not emerge with RT inhibitors nor decrease RT inhibitor susceptibility. Q145M should not, therefore, be considered an RT inhibitor resistance mutation.

Topics: Amino Acid Sequence; Anti-HIV Agents; Drug Resistance, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Nucleosides; Phenotype; Reverse Transcriptase Inhibitors

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques.

Topics: Adenine; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Organophosphonates; Phenotype; Plasmids; Tenofovir; Viral Load

Human leukocyte antigen allele (HLA)-B*5701 is associated with abacavir hypersensitivity. However, the carriage rate of HLA-B*5701 has rarely been studied in Asians. In 534 Korean patients with human immunodeficiency virus infection, HLA-B*5701 status was determined by polymerase chain reaction with HLA-B*5701-specific primers. No patients had the HLA-B*5701 allele (95% confidence interval, 0%-0.7%). This explains the paucity of immunologically confirmed cases of abacavir hypersensitivity in Koreans.

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Ethnicity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Korea; Male; Middle Aged; Polymerase Chain Reaction

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Topics: Adolescent; Age Factors; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Young Adult

Topics: Dideoxynucleosides; Drug Approval; Drug Combinations; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Both the safety and efficacy of this NRTI were drawn into question in 2008.

Topics: Dideoxynucleosides; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Positive data emerged this year to support the use of boosted atazanavir and boosted darunavir in treatment-naive patients. Raltegravir also looks promising in this population.

Topics: Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors

Topics: Child; Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blepharoptosis; Carbamates; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Oculomotor Muscles; Organophosphates; Organophosphonates; Sulfonamides; Tenofovir

Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged.. We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years).. Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years).. In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anti-HIV Agents; Clinical Trials as Topic; Coronary Artery Disease; Data Interpretation, Statistical; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Young Adult

Topics: Adiponectin; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; HIV Infections; Humans; Nevirapine; Receptors, Tumor Necrosis Factor, Type II

The most serious adverse event caused by abacavir is the hypersensitivity reaction, which is usually associated with the presence of the human leukocyte antigen (HLA) subtype B*5701, as shown in recent studies. We describe the case of a 41-year-old Caucasian female patient, who tested HLA-B*5701 negative and developed fever and severe skin rash 10 weeks after the start of abacavir therapy. Similar reports suggest that not all severe abacavir-induced adverse events occur as a result of classic hypersensitivity reactions, and can present also in HLA-B*5701-negative patients.

Topics: Adult; Dideoxynucleosides; Exanthema; Female; Fever; HIV Infections; HIV-1; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

HLA-B*5701 is strongly related to abacavir hypersensitivity reactions (HSRs). Polymorphisms at position 245 of HIV type-1 (HIV-1) reverse transcriptase (RT) show an association with HLA-B*5701 suggesting that viral genotyping performed for antiretroviral drug resistance testing could reduce human leukocyte antigen (HLA) screening necessity to prevent abacavir HSR.. To further test the validity of 245 codon analysis results for predicting HSR, we analysed 1,179 sequences from 752 HIV-1-infected patients.. Mutant amino acid residues in RT 245 were found in 30.6% of sequences. Among 239 patients with multiple longitudinal genotypes, 245 residues varied in 37 (15.5%) from wild type to mutant and/or vice versa. All these changes appeared during antiretroviral treatment. A total of 15 out of 229 (6.5%) abacavir-treated patients developed a clinically confirmed HSR: all carried B subtypes. There was no significant difference in the prevalence of 245 mutants between abacavir-treated patients with HSR (27%) and those without (29%), even after limiting the analysis to subtype B carriers.. The significant intraindividual variability of 245 residues and the lack of their association with clinically confirmed HSR argue against their use as viral genetic markers to exclude patients at risk for HSR.

Topics: Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; HLA-B Antigens; Humans; Mutation; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; RNA, Viral; Sequence Analysis, DNA; Sequence Analysis, RNA

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cardiovascular Diseases; Dideoxynucleosides; Drug Interactions; HIV Infections; Humans; Interleukin-2; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium

We investigated the virologic and immunologic responses to a mono-class, nucleoside/nucleotide reverse transcriptase inhibitor - combination therapy consisting of tenofovir and zidovudine/lamivudine/abacavir in therapy experienced patients.. Retrospective study of 122 patients. Primary analysis was performed at 48 weeks. Virologic response was defined as viral load levels less than 400 copies/ml.. About half of the patients had switched to tenofovir+ zidovudine/lamivudine/abacavir for simplification purposes or toxicity while the other half had experienced virologic failure. 80/122 (66%) responded. Median viral load decreased to 78 copies/ml at week 48; median CD4 count increased to 321 cells/mm(3). Of the 42 virologic failures, only 3 patients failed after week 24. 24/35 patients who had been on a non-suppressive zidovudine/lamivudine/abacavir-only regimen at baseline and added tenofovir to intensify, responded. 41/53 patients who switched from any nucleoside reverse transcriptase inhibitor-only regimen improved or maintained suppression. Genotypes were available for 85/122 patients. The only predictor of virologic failure was the combination 41L+210W+215Y/F mutational pattern. 16 of the patients who failed on tenofovir+ zidovudine/lamivudine/abacavir therapy selected new primary nucleoside reverse transcriptase inhibitor resistance mutations that they previously did not have. 48/85 (56%) patients with genotype tests had at least 3 (3-10; median 4) nucleoside reverse transcriptase inhibitor resistance-associated mutations in the past.. Patients heavily pre-treated with nucleoside analogues may show response to mono-class tenofovir+ zidovudine/lamivudine/abacavir therapy despite having a history of failure with nucleoside reverse transcriptase inhibitors. Lower baseline viral load, higher baseline CD4 count were significant predictors for response. Archived 41L+210W+215Y/F mutational pattern was significantly associated with non-response.

Topics: Adenine; Amino Acid Substitution; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation, Missense; Organophosphonates; Retrospective Studies; Salvage Therapy; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

The discovery of new associations between drug toxicities and specific HLA alleles has been facilitated by the use of DNA-based molecular techniques and the introduction of higher-resolution HLA typing, which have replaced serological typing in this field of study. Drug toxicity/HLA associations have been best documented for immunologically mediated reactions, such as drug hypersensitivity reactions associated with the use of abacavir, and severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis induced by carbamazepine and allopurinol use, respectively. The implementation of HLA-B*5701 screening for the prevention of abacavir hypersensitivity syndrome (ABC HSR) has provided a model approach that can be applied to the screening of other drugs. High-level clinical evidence supporting HLA-B*5701 screening for ABC HSR has converged with experimental findings characterizing the CD8+T-cell HLA-B*5701-restricted immune response triggered by abacavir. This has been followed by the successful development of simplified inexpensive and quality-assured laboratory tests for HLA-B*5701 and ongoing quality assurance programs, resulting in a paradigm both for the implementation of HLA-B*5701 screening for HIV providers as well as for the broader successful implementation of pharmacogenetic screening in the clinic.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Histocompatibility Antigens; HIV Infections; Humans; Pharmacogenetics

Several reports have indicated that patients with low CD4+ cell count could be at a higher risk for arterial lesions or cardiovascular disease (CVD). Recently, current use of abacavir has been associated with an excess risk of CVD. High sensitivity-C-reactive protein and interleukin-6 levels were high for patients receiving the drug. These data lead to the hypothesis that alternative mechanisms may be at work other that those linked to lipid changes and "classic" risk factors for atheroma. Consequently, we investigated the ultrasound characteristics of carotid plaques in HIV-positive patients comparing the results with those obtained from patients affected by atherosclerosis and patients with arteritis. The study population included 110 HIV-positive patients and 91 HIV-negative patients (61 atherosclerotic patients and 30 with arteritis). All patients were subjected to ultrasonography of the epi-aortic vessels. When compared to atherosclerotic patients, there was a significantly higher proportion of HIV-positive patients with hypoechogenic and homogeneous lesions, uniform in their parietal and endoluminal portions with a smooth or slightly irregular surface. No significant differences were found between HIV-positive and arteritis patients. This ultrasonographic study confirms that inflammatory mechanisms could play a major role in the onset of vascular damage in HIV-1 positive patients.

Topics: Adult; Anti-HIV Agents; Arteritis; Atherosclerosis; C-Reactive Protein; Dideoxynucleosides; Female; HIV Infections; Humans; Interleukin-6; Male; Middle Aged; Ultrasonography

HIV-infected patients have accelerated atherosclerosis. Abacavir has been associated with increased risk of cardiovascular events, for reasons that remain to be elucidated. As endothelial dysfunction is central to the pathogenesis of atherosclerosis, we tested the hypothesis that current treatment with abacavir is associated with impaired endothelial function.. We studied a cohort of 61 antiretroviral-treated patients who had undetectable plasma HIV RNA levels. Endothelial function was assessed by measuring flow-mediated dilation (FMD) of the brachial artery. We compared FMD in patients treated with or without abacavir, while adjusting for traditional risk factors and HIV-specific characteristics.. The median age was 50 years (interquartile range 45-57). The median duration of HIV infection was 18 years, and the median CD4 cell count was 369 cells/microl. Thirty patients (49%) were receiving abacavir. Overall, the median FMD in the HIV-infected patients was low (3.5%; interquartile range 2.3-5.6%). The FMD was lower in the abacavir-treated patients than those not on abacavir (2.8 vs. 4.9%, P = 0.01). After adjustment for traditional risk factors, HIV-specific factors, and baseline brachial artery diameter, current abacavir use was independently associated with lower FMD (P = 0.017). Duration of therapy and CD4 cell count were not associated with reduced FMD.. Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir-treated patients.

Topics: Anti-HIV Agents; Brachial Artery; Dideoxynucleosides; Endothelium, Vascular; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; RNA, Viral; Ultrasonography; Vasodilation; Viral Load

Topics: Dideoxynucleosides; Drug Hypersensitivity; Flow Cytometry; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Mass Screening; Pharmacogenetics; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

Patients with a baseline viral load >100,000 copies/mL receiving abacavir (ABC) as part of the nucleoside-backbone component of their first highly active antiretroviral therapy (HAART) regimen have been reported to have a greater failure rate than those receiving tenofovir (TDF). We analyzed short-term outcomes of the use of HAART combinations that included ABC or TDF. The mean 2-8-week change in viral load was calculated using linear regression. In total, 1136 patients started ABC, and 412 started TDF. After adjustment for baseline viral load and other factors, there was no difference in the change in viral load between the patients who started ABC and those who started TDF (0.03 [95% confidence interval, -0.07 to 0.12]) log copies/mL; P = .59). Furthermore, there was no evidence that this effect differed according to baseline viral load (P = .88 for the interaction between pre-HAART viral load and nucleoside started). Likewise, there was no difference in rates of virological failure between the 2 drugs at 24-48 weeks after starting HAART.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Tenofovir; Treatment Failure; Treatment Outcome; Viral Load

In treatment-naïve patients, a combination antiretroviral therapy (cART) containing tenofovir (TDF) and abacavir (ABC) with lamivudine leads to unacceptably high virological failure rates with frequent selection of reverse transcriptase mutations M184V and K65R. We explored the efficacy of at least 16 weeks of ABC + TDF-containing cART regimens in 307 antiretroviral-experienced HIV-1-infected individuals included in observational databases.. Virological failure was defined as an HIV RNA > 400 copies/ml after at least 16 weeks of treatment. Patients had received a median of three prior cART regimens. Of these, 76% concomitantly received a potent or high genetic barrier regimen (with at least one protease inhibitor [PI]) or non-nucleoside reverse transcriptase inhibitor or thymidine analogue) while a third non-thymidine nucleoside analogue was used in the remaining patients.. The 1-year estimated probability of virological failure was 34% in 165 patients with HIV RNA > 400 copies/ ml at ABC + TDF regimen initiation. Independent predictors of virological failure were the absence of a potent or high genetic barrier cART, the higher number of cART regimens experienced, and the use of a new drug class. In the subset of 136 patients for whom there were genotypic resistance test results prior to ABC + TDF initiation, the virological failure (1-year estimated probability 46%) was independently predicted by the higher baseline viral load, the concomitant use of boosted PI, and the presence of reverse transcriptase mutation M41L. In 142 patients starting ABC + TDF therapy with HIV RNA pound < or =400 copies/ml, virological failure (1-year estimated probability 17%) was associated only with the transmission category. In a small subset of subjects for whom there were an available paired baseline and follow-up genotype (n = 28), the prevalence of most nucleoside analogue reverse transcriptase inhibitor resistance mutations decreased, suggesting a possible low adherence to treatment. No selection of K65R was detected.. The virological response to ABC + TDF-containing regimens in this moderately-to-heavily treatment experienced cohort was good. Higher viral load and the presence of M41L at baseline were associated with worse virological responses, while the concomitant prescription of drugs enhancing the genetic barrier of the regimen conveyed a reduced risk of virological failure. The Appendix provides the names of other members of the MASTER cohort.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation, Missense; Organophosphonates; Tenofovir; Treatment Failure; Treatment Outcome; Viral Load; Viral Proteins

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two variants on a spectrum of severe systemic hypersensitivity characterized by blistering maculopapular lesions and desquamation of the skin and mucus membranes. Although several causative agents, including infections, have been reported for SJS/TEN, medications remain the most common cause. We report the case of a 42-year-old man with human immunodeficiency virus (HIV) who developed TEN 4 months after starting treatment with darunavir and abacavir. The patient presented with upper body lesions, oral mucosal ulcerations, and impending airway compromise. He was intubated and admitted to the burns unit. Score for Toxic Epidermal Necrolysis (SCORTEN) was 5, with > 90% predicted mortality. However, after intravenous immunoglobulin and supportive treatment, the patient made a remarkable recovery. Abacavir and darunavir may be associated with SJS/TEN. TEN should be considered a risk for patients with HIV and should be monitored for cutaneous eruptions for several months after changes in treatment regimen.

Topics: Adult; Antiviral Agents; Darunavir; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Immunoglobulins, Intravenous; Male; Risk Factors; Stevens-Johnson Syndrome; Sulfonamides; Treatment Outcome

Screening for HLA-B 5701 reduces the risk of developing an abacavir hypersensitivity reaction (ABC HSR) and is recommended in all patients before initiating highly active antiretroviral therapy (HAART) with abacavir. Between September 2007 and March 2008 we conducted a study of the attitudes and practice patterns of HIV providers in the United States to identify barriers to HLA-B 5701 testing in clinical practice. Study participants who completed an educational program could receive HLA-B 5701 test kits for use in their clinical practice. Surveys were administered before and after the educational program. A total of 477 HIV providers registered to participate in the survey, and 134 providers tested a total of 874 HIV-infected subjects, of which 6% (49/874) were HLA-B 5701 positive. Of 433 providers who completed the preeducation survey, 97% indicated that the test provided clinical value and 77% anticipated barriers to testing, with cost/reimbursement the most frequently cited. Among 202 providers who completed the posteducation survey, perceptions of the test's value remained largely unchanged while the proportion of providers who anticipated or encountered barriers to testing decreased. Of providers who used HLA-B 5701 test kits, 86% (115/134) found it "very easy" or "easy" to obtain test results, 95% (127/134) found it "very easy" or "easy" to interpret results, and 89% (119/134) indicated that they planned to continue HLA-B 5701 testing after the study. The results of this study suggest that HLA-B 5701 testing is easy to use in clinical practice and is a valuable tool to help reduce the risk of developing ABC HSR.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Attitude of Health Personnel; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Histocompatibility Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors; United States

To investigate, using a longitudinal design, whether biomarkers of cardiovascular risk change after a switch to an abacavir (ABC)-containing regimen in HIV-1-infected individuals already receiving combination antiretroviral therapy (ART).. Thirty-five HIV-1-infected individuals who switched ART to an ABC-containing regimen were identified. Twenty-two HIV-1-infected individuals who switched ART from and to a non-ABC-containing regimen served as controls. Plasma concentrations of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), matrix metallopeptidase 9 (MMP9), myeloperoxidase (MPO) and high sensitivity C-reactive protein (hs-CRP) were measured in blood samples before the switch in ART, and 3 months and 12 months afterwards. Log10-transformed data were compared with paired t-tests.. Median MMP9 increased from 45.5 to 64.4 microg/mL after 3 months of ABC exposure (P = 0.011) and remained increased after 12 months (64.2 microg/mL; P = 0.013). MPO increased from median 8.8 to 10.4 microg/mL (P = 0.036) after 3 months of ABC exposure but was not increased after 12 months of exposure (9.1 microg/mL). hs-CRP increased from 3.3 to 4.2 microg/mL after 3 months (P = 0.031) but was not increased after 12 months of exposure (2.8 microg/mL). Neither sVCAM-1 nor sICAM-1 changed after the initiation of ABC. No changes were observed in the control group.. MMP9, MPO and hs-CRP all increased after a switch in ART to an ABC-containing regimen. This indicates increased cardiovascular risk in viral load-suppressed HIV-1-infected individuals switching to ABC and proposes a proinflammatory potential as the underlying pathogenetic mechanism.

Topics: Adult; Aged; Anti-Retroviral Agents; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Intercellular Adhesion Molecule-1; Longitudinal Studies; Male; Matrix Metalloproteinase 9; Middle Aged; Peroxidase; Risk Factors; Vascular Cell Adhesion Molecule-1; Viral Load; Zidovudine

Topics: Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Tablets; United States; United States Food and Drug Administration; Zidovudine

Topics: Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brachial Plexus Neuritis; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Reverse Transcriptase Inhibitors

Topics: Black People; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV).. All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4.. A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/microl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31-4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50-14.29], < 0.001) and lower RBV plasma trough concentrations (1.74 per microg/ml [1.15-2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91-5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels < 2.3 microg/ml (7.63 [1.39-41.67], 0.02).. The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.

Topics: Adult; Antiviral Agents; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Odds Ratio; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Reverse Transcriptase Inhibitors; Ribavirin; Risk Assessment; RNA, Viral; Spain; Treatment Failure; Viral Load

The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase can be selected by abacavir, didanosine, tenofovir, and stavudine in vivo resulting in reduced susceptibility to these drugs and decreased viral replication capacity. In clinical isolates, K65R is frequently accompanied by the A62V and S68G reverse transcriptase mutations.. The role of A62V and S68G in combination with K65R was investigated using phenotypic, viral growth competition, pre-steady-state kinetic, and excision analyses.. Addition of A62V and S68G to K65R caused no significant change in human immunodeficiency virus type 1 resistance to abacavir, didanosine, tenofovir, or stavudine but partially restored the replication defect of virus containing K65R. The triple mutant K65R+A62V+S68G still showed some replication defect compared with wild-type virus. Pre-steady-state kinetic analysis demonstrated that K65R resulted in a decreased rate of incorporation (kpol) for all natural dNTPs, which were partially restored to wild-type levels by addition of A62V and S68G. When added to K65R and S68G, the A62V mutation seemed to restore adenosine triphosphate-mediated excision of tenofovir to wild-type levels.. A62V and S68G serve as partial compensatory mutations for the K65R mutation in reverse transcriptase by improving the viral replication capacity, which is likely due to increased incorporation efficiency of the natural substrates.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Organophosphonates; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Virus Replication

Topics: Didanosine; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors; United States; United States Food and Drug Administration

Topics: Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors

Hypersensitivity reactions to abacavir occur in 5-8% of patients starting treatment with this drug and limits future treatment. Some host genetic factors, especially the HLA-B*5701 allele, have been identified as risk factors for hypersensitivity reaction in Caucasians. Consequently, the possibility of routine implementation of a genetic test to rule out the presence of this allele has been proposed to achieve a personalized therapeutic profile. The present article discusses all the information related to hypersensitivity to abacavir and its genetic and immunological markers, as well as the distinct techniques for HLA-B*5701 allele detection. The various studies performed to date in distinct population are also discussed.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans

Topics: Anti-HIV Agents; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Drug Labeling; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

The aim of the study was to investigate the incidence of abacavir-related hypersensitivity reaction (HSR) and associated deaths in EuroSIDA HIV-1-infected patients.. Poisson regression models were developed to compare incidence of abacavir discontinuation according to the line of therapy within which abacavir was received, geographical regions, calendar time and drug formulation (abacavir/lamivudine combination tablet versus abacavir as a single drug or abacavir/zidovudine/lamivudine combination).. Of 3,278 patients that started abacavir, 2,101 (64.1%) discontinued. Of these, 167 (5.1%) discontinued abacavir within 3 months due to HSR with an incidence of 22.1 (95% confidence interval [CI] 18.7-25.4) per 100 person-years of follow-up. After adjustment for gender, prior AIDS, hepatitis C serostatus, baseline CD4+ T-cell count, region and calendar time, HSR incidence was significantly higher in those starting abacavir in a first-line regimen compared with second-line (incidence rate ratio [IRR] 2.04 [95% CI 1.24-3.38]; P=0.005). There was no significant difference between regions. HSR incidence from 2005 onwards was significantly lower compared with 1999-2000 (IRR 0.54 [95% CI 0.32-0.92]; P=0.024). There was a lower observed incidence in patients starting abacavir/lamivudine compared with other formulations (IRR 0.33 [95% CI 0.13-0.88]; P=0.027), however, available data were limited.. Incidence of abacavir-related HSR is higher in patients starting abacavir in first-line therapy, which could indicate increased over-diagnosis. HSR incidence has decreased in recent years, which might reflect the wider availability of genetic screening and improved awareness of symptoms. There were no reported deaths due to abacavir HSR.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Europe; Female; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Male; Middle Aged; Poisson Distribution; Reverse Transcriptase Inhibitors; Treatment Outcome; Zidovudine

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Failure, Chronic; Proteinuria

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Endothelium, Vascular; HIV Infections; Humans; Myocardial Infarction; Nucleotidases

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans

To evaluate the clinical impact and cost-effectiveness of HLA-B*5701 testing to guide selection of first-line HIV regimens in the United States.. Cost-effectiveness analysis using a simulation model of HIV disease. The prevalence of HLA-B*5701 and the probabilities of confirmed and unconfirmed severe systemic hypersensitivity reaction among patients taking abacavir testing HLA-B*5701 positive and negative were from the Prospective Randomized Evaluation of DNA Screening in a Clinical Trial study. The monthly costs of abacavir-based and tenofovir-based regimens were $1135 and $1139, respectively; similar virologic efficacy was assumed and this assumption was varied in sensitivity analysis.. Simulated cohort of patients initiating HIV therapy.. The interventions are first-line abacavir, lamivudine, and efavirenz without pretreatment HLA-B*5701 testing; the same regimen with HLA-B*5701 testing; and first-line tenofovir, emtricitabine, and efavirenz.. Quality-adjusted life years and lifetime medical costs discounted at 3% per annum, cost-effectiveness ratios ($/QALY).. Abacavir-based treatment without HLA-B*5701 testing resulted in a projected 30.93 years life expectancy, 16.23 discounted quality-adjusted life years, and $472,200 discounted lifetime cost per person. HLA-B*5701 testing added 0.04 quality-adjusted months at an incremental cost of $110, resulting in a cost-effectiveness ratio of $36,700/QALY compared with no testing. Initiating treatment with a tenofovir-based regimen increased costs without improving quality-adjusted life expectancy. HLA-B*5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment. Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of HLA-B*5701.. Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Dideoxynucleosides; Drug Costs; Drug Hypersensitivity; Female; Genetic Testing; Health Care Costs; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Models, Biological; Organophosphonates; Pharmacogenetics; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Tenofovir; Treatment Outcome

The aim of this work was to analyze pH and sugar concentration in seven antiretroviral and three antibacterial medications frequently prescribed to HIV infected paediatric patients.. Sugars (sucrose, glucose, lactose and fructose) and pH were measured from every one of ten medications with different serial numbers in two samples. The pH was determined by a previously calibrated digital pHmeter (Beckman). Analysis of free sugars was performed using thin-layer chromatography (TLC). The pH results and the amount of sugar originated from the two samples in each lot were added. The arithmetic mean of these results were computed.. Two antiretrovirals (Zidovudin and Abacavir Sulphate) had pH below critical level (3.55 and 3.93, respectively). All three antibacterials analyzed had pH above 5.5, and one of them (Azithromycin) had the highest pH level of the ten medications examined (9.28). Sugar was present in seven out of 10 of the medications analyzed. The antibacterials contained the highest concentration of sucrose, ranging from 40% to 54%. Glucose was found in one of the ten, sucrose was present in seven of them and none showed lactose. Fructose was not observed with the technique used.. A number of medications frequently used by HIV-infected children may cause a significant risk of both caries and dental erosion.

Topics: Amoxicillin; Anti-Bacterial Agents; Anti-HIV Agents; Azithromycin; Cariogenic Agents; Chromatography, Thin Layer; Dental Caries; Dideoxynucleosides; Fructose; Glucose; HIV Infections; Humans; Hydrogen-Ion Concentration; Lactose; Sucrose; Tooth Erosion; Zidovudine

Abacavir is a potent nucleoside analog reverse transcriptase inhibitor approved for the treatment of HIV infection. Approximately 5-8% of Caucasian patients receiving abacavir develop a hypersensitivity reaction, characterized by rash, fever and, occasionally, multisystemic involvement. Rechallenge with the drug can be fatal. The discovery of the mechanisms involved in this hypersensitivity reaction and the identification of tools for its prediction are the subject of this review. The most relevant finding is the recognition of a strong association between one specific haplotype at the HLA complex type I, HLA-B*5701, and the abacavir hypersensitivity reaction. The heterogeneity in the prevalence of HLA-B*5701 across distinct ethnicities accounts for differences in the risk of abacavir hypersensitivity reactions in distinct populations.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Forecasting; Genetic Testing; Haplotypes; HIV Infections; HLA-B Antigens; Humans; Models, Immunological; Reverse Transcriptase Inhibitors; Risk Factors; Sensitivity and Specificity

Topics: Dideoxynucleosides; Drug Approval; Drug Combinations; Drugs, Generic; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Topics: Biomarkers, Pharmacological; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Longitudinal Studies; Male; Myocardial Infarction; Reverse Transcriptase Inhibitors

Topics: Adult; Chemical and Drug Induced Liver Injury; Dideoxynucleosides; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; Humans; Liver Function Tests; Reverse Transcriptase Inhibitors; Treatment Outcome

Topics: Anti-HIV Agents; Child; Dideoxynucleosides; Drug Approval; Drugs, Generic; HIV Infections; HIV-1; Humans; Lamivudine; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

The combination of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is the standard of care for hepatitis C virus (HCV) treatment in HIV-coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was, for the first time, reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the effect of ABC on the response rate to HCV therapy.. A retrospective analysis of HIV-HCV-coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. An analysis of baseline descriptive variables was conducted. Logistic regression models were used to test possible associations between non-response and pretreatment characteristics, including antiretroviral drugs.. A total of 244 HIV-HCV-coinfected patients treated with PEG-IFN and RBV were included. Overall, 85% of patients were on highly active antiretroviral therapy; of these patients, 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was 213.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached a sustained virological response (SVR; 46.2% in ABC group versus 46.7% in non-ABC group, P=1). The only two factors in the multivariate analysis that were statistically associated with an increased risk of failure to achieve SVR were HCV genotypes 1 or 4 and older age. The use of ABC was not associated with failure to achieve SVR at any of the other time points evaluated.. Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affect the outcome of this treatment.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Dideoxynucleosides; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Interferon alpha-2; Interferon-alpha; Male; Polyethylene Glycols; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin; Treatment Outcome

We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting.. We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods.. From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment.. HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.

Topics: Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Variation; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Switzerland

Topics: Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors

The aim of the study was to determine the factors that may contribute to decreases in bone mineral density (BMD) in patients with AIDS.. This was a prospective, non-randomized study. Dual X-ray absorptiometry (DXA) was used to determine the BMD of the lumbar spine, femoral neck and distal radius in treatment-naïve HIV-infected male patients with AIDS before and after 1 year of treatment with zidovudine (ZDV)/lamivudine (3TC) plus abacavir (ABC) or lopinavir/ritonavir (LPV/r).. Basal DXA was performed in 50 patients with CD4 counts <200 cells/microL and/or any AIDS-defining condition. Thirty-two patients completed 1 year with full adherence (17 on ABC and 15 on LPV/r) and a second DXA was then performed. At baseline, 19% had osteopenia at the lumbar spine and 19% at the femoral neck. Low body weight was related to low BMD. After 48 weeks, BMD loss was significant at the three locations. The percentage of BMD loss at the femoral neck tended to be greater in the lopinavir group (5.3 vs. 3.2%, P=0.058). The differences became significant at the lumbar spine (5.7 vs. 2.7%, P=0.044). In the multivariate analysis, the treatment with LPV/r remained associated with bone loss at the lumbar spine.. Osteopenia is frequent in treatment-naïve HIV-infected men with AIDS. Bone loss is higher with LPV/r-based regimens compared with triple nucleoside reverse transcriptase inhibitors.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Case-Control Studies; Dideoxynucleosides; Femur Neck; HIV Infections; Humans; Lamivudine; Lopinavir; Lumbar Vertebrae; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Zidovudine

To investigate the concordance between any of the results of nine HIV-1 drug-resistance interpretation systems (ISs) and their ability to predict week 8 and week 24 virological responses to abacavir-containing combination therapy.. A total of 1306 HIV-infected patients with a viral load >500 HIV-1 RNA copies/mL and a baseline genotypic resistance test were included in the study. Predicted abacavir susceptibilities according to each rule-based IS were compared. Linear and logistic regressions were used to assess the prognostic value of each IS for week 8 and week 24 responses, respectively.. A median of three (interquartile range 1-5) abacavir mutations were detected at baseline. Comparing the IS predictions for abacavir susceptibility, 9% to 45% of patients were predicted to have resistant (R) virus, 9% to 53% virus with intermediate (I) resistance, and 23% to 74% susceptible (S) virus. Overall, the median week 8 viral load reduction was 1.61 log(10) copies/mL (95% confidence interval 1.52-1.71) and 50% of patients experienced virological failure at 24 weeks. Most ISs showed better virological responses with S and I viruses than with R viruses.. Despite some degree of variability in predicted abacavir susceptibility among ISs, most ISs are useful to predict virological response.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; RNA, Viral; Viral Load

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Risk Factors

Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients.. We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals.. Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir).. There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

Topics: Adult; Aged; Aged, 80 and over; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Poisson Distribution; Reverse Transcriptase Inhibitors; Risk Factors

Human immunodeficiency virus (HIV) has caused resurgence in tuberculosis (TB) worldwide. HIV-TB coinfected individuals are at increased risk for complications of TB and HIV treatment, such as adverse drug reactions and immune reconstitution syndrome. A 17-year-old male with HIV-TB coinfection, who developed cardiac tamponade from immune reconstitution during treatment for TB and HIV, is reported in this document.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiac Tamponade; Comorbidity; Dideoxynucleosides; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; Male; Pericardial Effusion; Tuberculosis, Pulmonary; Ultrasonography

Topics: Anti-HIV Agents; Australia; Didanosine; Dideoxynucleosides; Europe; Heart Diseases; HIV Infections; HIV-1; Humans; Myocardial Infarction; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors

Topics: Anti-HIV Agents; Chemistry, Pharmaceutical; Child; Child, Preschool; Dideoxynucleosides; Drug Approval; Drug Combinations; European Union; HIV Infections; Humans; Infant; Infant, Newborn; Lamivudine; Reverse Transcriptase Inhibitors; Zidovudine

To evaluate the safety, immunological outcome and HIV-1 evolution in the reverse transcriptase (RT) in patients with multidrug resistance receiving zidovudine/lamivudine/abacavir (TZV) plus tenofovir (TDF).. Pilot analysis of highly experienced patients (n=28), with > or =1 thymidine-associated mutation (TAM) and the M184V mutation.. Median of 8.5 treatment regimens, 58% Centers for Disease Control stage C. Baseline (nadir) CD4 count 363 (112) cells/microL. There was a sustained 24-week drop in viral load (VL) of 0.71 HIV-1 RNA copies/mL (P<0.001), with 35.7% (10/28) achieving a VL of <50 copies/mL. The median 24-week decrease in CD4 was -53 cells/microL and only-17 cells/microL when baseline CD4 was <350 cells/microL. There was no evolution in RT mutations, TAMs, accessory mutations or K65R. No clinical progression and one out of 28 suspected abacavir Hypersensitivity Reaction (HSR). Lower probability of achieving VL<400 copies/mL was associated with D67N (P=0.007), D67N/M41L (P=0.01), > or =3 TAMs (P=0.07) and VL>10 000 copies/mL (P=0.01). Mutations conferring zidovudine hypersusceptibility (Y181C, K65R and L74V) did not improve virological or immunological outcomes. Better CD4 outcomes were seen in patients without M41L (P=0.04) or with baseline VL<10,000 copies/mL (P=0.01).. A bridging regimen with TZV+TDF prevents significant immunological decline and may forestall viral evolution in HIV-1 RT despite persistent viral replication.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Pilot Projects; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Thymidine; Viral Load; Zidovudine

Abacavir hypersensitivity in genetically susceptible individuals implicates an abacavir-specific T-cell response to either the parent drug or a metabolite generated in vivo. We have analysed the cytokine profile in antigen-presenting cells and the T-lymphocytes that are involved in the pathological immune response to abacavir.. In this study, we compared abacavir-specific cytokine responses in cultured peripheral blood mononuclear cells (PBMCs) from HIV-infected abacavir hypersensitive, tolerant and naive individuals. Cells were cultured in the presence or absence of abacavir. Cytokine expression was determined by microarray analysis, enzyme-linked immunosorbent assays and flow cytometry.. We demonstrated using in vitro models of immune activation that the production of interferon-gamma was specifically induced by abacavir treatment in PBMCs obtained from hypersensitive patients carrying the HLA-B*5701 allele (median 123.86 compared with -30.83 for tolerant controls, P=0.001).. These results provide further insight into the immunological and metabolic basis of abacavir hypersensitivity syndrome. In vitro assays could assist in the identification of susceptible loci by providing a surrogate marker for the hypersensitivity reaction. Such a marker could be studied in unexposed individuals to shed further light on the immunopathogenesis of the abacavir hypersensitivity syndrome.

Topics: Anti-HIV Agents; Cells, Cultured; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Black People; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; England; HIV Infections; HLA-B Antigens; HLA-B52 Antigen; Humans

Incomplete adherence is the main cause of antiretroviral therapy failure during initial combination antiretroviral therapy (cART). A switch to a protease inhibitor-sparing cART may be useful when a patient does not tolerate a first protease inhibitor-containing cART regimen.. To compare the biological and clinical outcomes of patients in whom a first protease inhibitor-containing cART regimen failed to control viral replication and whose treatment was switched to cART containing efavirenz, nevirapine, or abacavir, we studied 1440 patients from the French Hospital Database on HIV whose treatment was changed from a first protease inhibitor-containing cART to a 3-drug regimen with either efavirenz, nevirapine, or abacavir while their plasma viral load was detectable.. Kaplan-Meier 12-month probabilities of virological suppression were 73.6%, 53.9%, and 66.1% among patients whose treatment was switched to efavirenz-cART, nevirapine-cART, and abacavir-cART, respectively. Factors associated with a lower likelihood of virological suppression were antiretroviral exposure before the first cART, higher plasma viral load values at the treatment switch, a stavudine-lamivudine backbone after the switch (instead of a zidovudine-lamivudine backbone), and a switch to nevirapine (adjusted hazard ratio, 0.63 [95% CI, 0.54-0.74], compared with efavirenz) or abacavir (adjusted hazard ratio, 0.84 [95% CI, 0.68-1.04] compared with efavirenz). There was no difference among the 3 groups with regard to immunological gain (>50 CD4+ T cells/mm3) or clinical outcome.. When virological rebound occurs from receipt of protease inhibitor-containing cART, virological suppression can be obtained after a switch to a protease inhibitor-free cART--efavirenz-cART yielding the highest rate of virological suppression.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Oxazines; Protease Inhibitors; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Virus Replication

All nucleoside reverse transcriptase inhibitors (NRTI) must first be metabolized to their triphosphate forms in order to be active against HIV. Zidovudine (ZDV), abacavir (ABC) and lamivudine (3TC) have proven to be an efficacious combination. In order simultaneously to measure intracellular levels of the triphosphates (-TP) of ZDV, ABC (carbovir, CBV) and 3TC, either together or individually, we have developed a cartridge-LC-MS/MS method. The quantitation range was 2.5-250 pg/microl for 3TC-TP, 0.1-10.0 pg/microl for ZDV-TP and 0.05-5.00 pg/microl for CBV-TP. This corresponds to 0.1-11.0 pmol 3TC-TP per million cells, 4-375 fmol ZDV-TP per million cells and 2-200 fmol CBV-TP per million cells, extracted from 10 million cells. Patient samples demonstrated measured levels in the middle regions of our standard curves both at pre-dose and 4h post-dose times.

Topics: Chromatography, High Pressure Liquid; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Phosphates; Reference Standards; Reverse Transcriptase Inhibitors; Tandem Mass Spectrometry; Zidovudine

Abacavir is associated with an infrequent but potentially serious hypersensitivity reaction (HSR) that can include a wide range of signs and symptoms. Identification of this reaction through medical insurance claims could provide a simple and efficient means of monitoring the incidence of abacavir hypersensitivity in large populations of patients.. Using data from a safety study of 948 abacavir users with 22 hypersensitivity events identified from claims and validated through medical record review, we used a recursive partitioning analysis to construct an algorithm to differentiate between patients with and without validated adverse events. Bootstrap resampling techniques provided validation for the analysis.. The analysis produced a classification tree with three decision nodes that comprised the best indicators of HSRs. The predictors included any one of several specific symptoms commonly found with this reaction, a claims diagnosis of adverse effect of drug, anaphylactic shock or unspecified allergy, and a discontinuation in abacavir prior to completing a 90-day course of therapy. The algorithm demonstrated 95% sensitivity and 90% specificity when tested using a bootstrap resampling approach with the current data.. A sensitive and specific algorithm for identifying abacavir hypersensitivity from claims was created. This algorithm would permit efficient identification of charts for medical review. Further testing of the algorithm with additional medical claims data for abacavir users will be required to ascertain its validity across databases.

Topics: Algorithms; Anti-HIV Agents; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Insurance Claim Reporting; Male; Regression Analysis; Sensitivity and Specificity

A 36-year-old man with HIV infection developed a reaction compatible with an abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation. The switch was determined by a more convenient intake. The patient was treated with abacavir twice-daily plus lamivudine and efavirenz for more than 5 years with no side effects. At the time of this change, his CD4 count was 1069 cell/mm(3) and HIV-RNA undetectable. Our case suggests that patients should be carefully monitored after switching, and warned about the potential effects.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; HIV Infections; Humans; Lamivudine; Male; Oxazines; RNA, Viral

To improve adherence and virologic suppression, we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1-infected children.. HIV-1-infected children naive to efavirenz were treated with a combination of efavirenz, abacavir, didanosine, and lamivudine in an observational, prospective, single-center study. Virologic failure-free survival was assessed with Kaplan-Meier analysis. The CD4+ T-cell increase was estimated by using a generalized linear model incorporating repeated measurements.. Thirty-six children received the study medication for a median of 69 weeks. Virologic failure-free survival rates were 76% and 67% after 48 weeks and 96 weeks, respectively. No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy. All children receiving highly active antiretroviral therapy showed a sustained CD4+ T-cell increase, irrespective of virologic suppression. Growth rates improved with highly active antiretroviral therapy. Study medication administration was stopped for 14 children, mostly because of nonadherence (4 cases) or virologic rebound (5 cases) and because of adverse events (unrelated death and grade 2 liver toxicity) in 2 cases. Lipid abnormalities and abacavir-related hypersensitivity were not observed.. For the first time, once-daily highly active antiretroviral therapy is demonstrated to be a safe, convenient, and potent antiretroviral regimen for HIV-1-infected children.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child Development; Child, Preschool; Cholesterol; Cohort Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Male; Oxazines; Patient Compliance; Prospective Studies; Treatment Outcome

The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Evaluation, Preclinical; Drug Hypersensitivity; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Pharmacogenetics; Predictive Value of Tests

The association of human leukocyte antigen-B*5701 with abacavir hypersensitivity varies depending on ethnic origin. We confirmed the high specificity of B*5701 in the ethnically mixed French population and used a rapid and inexpensive polymerase chain reaction strategy to evaluate the predictiveness of B*5701 screening. The incidence of hypersensitivity decreased from 12% before screening to 0% after screening, and the rate of unwarranted interruptions of abacavir therapy decreased from 10.2% to 0.73%. We therefore recommend the implementation of this cost-effective screen before treatment with abacavir.

Topics: Anti-HIV Agents; Black People; Dideoxynucleosides; Female; France; Genetic Testing; HIV; HIV Infections; HLA-B Antigens; Humans; Hypersensitivity; Incidence; Male; Middle Aged; Polymerase Chain Reaction; Predictive Value of Tests; Prospective Studies; Retrospective Studies; Sensitivity and Specificity; Suburban Population; Urban Population; White People

We previously described chimeric HIV-1, EcoHIV, which can infect mouse cells in culture and cause spreading infection in conventional immunocompetant mice. We have now applied this system as a model for preclinical evaluation of anti-retroviral drugs.. We used chimeric virus EcoHIV/NDK constructed on the backbone of subtype D NDK. EcoHIV/NDK expression in mice was characterized 5-10 days after infection by testing viral DNA, RNA, and protein burdens in spleen and macrophages by real-time PCR (QPCR), RT-PCR, and p24 ELISA. For antiviral evaluation, groups of 5-7 mice were pretreated with 2',3'-dideoxycytidine (ddC), abacavir, or vehicle; mice were then infected with EcoHIV/NDK, treatment maintained for additional 48 h, and tested for viral DNA and RNA burdens in spleens and macrophages by QPCR.. EcoHIV/NDK infected mice reproducibly showed viral burdens of up to 1.4 x 10 viral DNA copies and 200 pg p24 per 10 spleen cells and expressed spliced Vif RNA and mature p24 in macrophages 5-10 days after infection. Treatment of mice with 60 or 300 mg ddC/kg/day blocked EcoHIV/NDK infection in a dose-dependent manner with significantly lower viral DNA and RNA burdens at both drug doses (P < 0.001) in the spleens of infected mice. Abacavir tested at 100 mg/kg/day caused 96% inhibition of viral DNA synthesis in spleen and it almost completely abolished viral spliced RNA synthesis in spleens and macrophages.. The system of chimeric HIV-1 infection of mice permits rapid, statistically powerful, and inexpensive evaluation of antiretroviral drugs in vivo.

Topics: Animals; Anti-HIV Agents; Chimera; Dideoxynucleosides; Disease Models, Animal; DNA, Viral; Drug Evaluation, Preclinical; HIV Infections; HIV-1; Macrophages, Peritoneal; Mice; Polymerase Chain Reaction; Spleen; Viral Load; Zalcitabine

Topics: Anti-HIV Agents; Antiviral Agents; Bilirubin; Chi-Square Distribution; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Multivariate Analysis; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; RNA, Viral; Time Factors; Treatment Failure; Viral Load

The effects of HIV infection, highly active antiretroviral therapy (HAART), and specific antiretroviral agents on lipoproteins in women are not well described.. In a cross-sectional substudy of the Women's Interagency HIV Study with 623 HIV-negative and 1556 HIV-positive women (636 untreated, 419 on non-protease inhibitor [PI] HAART, and 501 on PI-containing HAART), we performed multivariate analyses of associations among fasting lipoprotein levels, HIV infection, and HAART.. Untreated HIV-positive women had lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TGs) but not lower low-density lipoprotein cholesterol (LDL-C) than HIV-negative women and were the most likely to have unfavorable HDL-C by National Cholesterol Education Program (NCEP) guidelines. PI HAART users had higher LDL-C than untreated HIV-infected women (107 vs. 100 mg/dL, P = 0.0006) and were the most likely to have unfavorable LDL-C and TGs by NCEP guidelines. HIV-negative women and non-PI HAART users had similar HDL-C levels (55 and 53 mg/dL, respectively), which were higher than those in untreated HIV-infected women and PI HAART users (42 and 49 mg/dL, respectively; P < 0.001 for all). Lamivudine, didanosine, nevirapine, and efavirenz were independently associated with higher HDL-C (P < 0.001 for all). Ritonavir, indinavir/ritonavir, and nelfinavir were associated with higher LDL-C (P < 0.01 for all). Stavudine, abacavir, and all ritonavir-containing regimens were associated with higher TGs (P < 0.05 for all), and tenofovir was associated with lower TGs (P = 0.009).. A dyslipidemic pattern was associated with HIV infection itself, was more severe in users of PI-containing HAART, but was not present in women taking non-PI HAART.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black People; Cholesterol; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Fasting; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Multivariate Analysis; Nelfinavir; Nevirapine; Organophosphonates; Ritonavir; Stavudine; Tenofovir; Triglycerides; United States; White People

We identified a deletion at codon 70 (Delta70) of HIV-1 reverse transcriptase (RT) occurring together with L74V and Q151M mutations in a sample from a tenofovir (TFV)- and abacavir (ABC)-treated patient with extensive prior antiretroviral treatment. To investigate the characteristics of this mutant, we studied the drug susceptibility, relative infectivity, and fitness of viruses carrying Delta70 and associated RT mutations. The Delta70, L74V, and Q151M mutations were introduced into Hxb2 RT by site-directed mutagenesis and expressed in HIV-1 recombinants. The Delta70 mutation increased resistance to lamivudine and emtricitabine alone and in combination with various resistance mutations and augmented resistance to ABC and didanosine when present together with L74V. A recombinant virus expressing RT from the original clinical viral sample (Delta70-PRT) exhibited greater fitness than one in which the deletion had been repaired (K70-PRT). The Delta70 mutation also increased fitness of Hxb2 wild-type and 74V and Q151M mutants. Recombinants carrying Delta70-PRT showed greater relative infectivity in the presence of ABC (but not TFV) compared with K70-PRT recombinants. These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background.

Topics: Adenine; Antiviral Agents; Cell Line, Transformed; Codon; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Emtricitabine; HeLa Cells; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Organophosphonates; Point Mutation; Reassortant Viruses; Reverse Transcriptase Inhibitors; Tenofovir

Topics: Acyclovir; Anti-HIV Agents; Circumcision, Male; Cyclohexanes; Dideoxynucleosides; Drug Interactions; Female; Hepatitis C; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Maraviroc; Multicenter Studies as Topic; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Triazoles

Topics: Bipolar Disorder; Dideoxynucleosides; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

HPV infections have become a major problem in immunocompromised patients, particularly in HIV-positive subjects. HPV lesions are observed more frequently in the ano-genital area and rarely in different body areas, such as the skin and oral cavity. However, in HIV-positive subjects there is an increased risk of oral condylomas. We describe the case of an HIV-positive Nigerian young woman, who came to our notice due to the appearance of small labial and mouth mucous membrane lesions, related to HPV infection, as shown by a biopsy. These lesions were not evident in the genital area. After two years in which the patient no longer received therapy, there was a progressive reduction in CD4 count, associated with the development of the oral condylomas. Hence the patient began a new HAART combination, but after seven months, although a slight improvement emerged in the CD4 count with the disappearance of HIV-RNA, there has been no regression of oral condylomas.

Topics: Adenine; Adult; Alphapapillomavirus; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Lamivudine; Lopinavir; Mouth Mucosa; Nigeria; Organophosphonates; Papillomavirus Infections; Pyrimidinones; Ritonavir; Sex Work; Stomatitis; Tenofovir; Treatment Refusal; Zidovudine

To describe the incidence of hypersensitivity to abacavir and frequency of human leucocyte antigen (HLA)-B*5701 in HIV-infected Taiwanese persons.. Medical records of 337 HIV-infected Taiwanese in whom abacavir-containing combination antiretroviral therapy (CART) was prescribed from 1 May 2001 to 31 December 2006 were reviewed, and HLA typing of the patients was performed in 320 patients (232 receiving abacavir and 88 not receiving abacavir) with available blood samples. HLA class I and II polymorphisms were determined by PCR with specific primers. HLA-B*5701 was further confirmed by sequence-based typing.. Of the 337 patients, median CD4 count was 166.5 cells/mm3 (range, 1.0-1914.0) and 83 patients (24.6%) had AIDS-defining opportunistic infections. Thirty-eight patients (11.3%) discontinued abacavir within 6 weeks of starting abacavir-containing CART. Among them, 10 patients had successful abacavir re-challenge and another 11 patients had other specific reasons for abacavir discontinuation. Therefore, 14 patients (4.2%) were classified as cases in whom abacavir hypersensitivity could not be excluded, and 3 patients (0.9%) met the criteria of abacavir hypersensitivity. Of the 320 patients undergoing HLA typing, HLA-A02 was the most common allele and only one individual (0.3%) expressed HLA-B*5701. Along with some differences in allele distributions, there was a significant difference in the genetic frequency of HLA-B57 in our patients compared with those of previous studies in other Chinese populations.. Abacavir hypersensitivity was less frequently encountered in HIV-infected Taiwanese initiating abacavir-containing CART than in Caucasians, which might be explained by the low frequency of the HLA-B*5701 allele.

Topics: Adult; Alleles; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA Antigens; HLA-B Antigens; Humans; Male; Polymorphism, Genetic; Taiwan; Terminology as Topic

Topics: Administration, Oral; Didanosine; Dideoxynucleosides; Drugs, Generic; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

Topics: Adult; Alkynes; Alopecia; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Probability; Pyrimidinones; Ritonavir

The aim of this study was to determine the incidence of abacavir discontinuation within the first two months of treatment and the link with a true hypersensitivity reaction (HSR).. A retrospective study was made between January 1998 and January 2006 on a cohort of HIV positive patients treated by abacavir delivered by the Bordeaux Saint-André University Hospital pharmacy.. Six hundred (and) twenty-eight patients were included. The reasons for non-renewal of abacavir prescription within the first three months of treatment were investigated. Early discontinuation for adverse effects was reported in 32 patients (5.1%): proved diagnosis of HSR (N=10), uncertain diagnosis of HSR (N=8), and no HSR (N=14). The decision for discontinuation was taken by physician after consultation in 76% of cases.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Fever; France; Gastrointestinal Diseases; HIV Infections; Hospitals, University; Humans; Musculoskeletal Diseases; Retrospective Studies

Abacavir is metabolized primarily by two enzymes: alcohol dehydrogenase and gluconyl transferase. Under normal conditions, alcohol is hepatically cleared via alcohol dehydrogenase to acetaldehyde, and subsequently by acetaldehyde dehydrogenase (ACD) to acetic acid. Disulfiram acts as an ACD blocker. Abacavir may also act as an inhibitor of alcohol dehydrogenase, which raises the possibility of disulfiram-like reactions (if complete inhibition occurs) or reduced alcohol tolerance (if partial inhibition occurs) occurring with abacavir therapy.

Topics: Adult; Alcohol Drinking; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Disulfiram; Ethanol; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

Triple nucleoside reverse transcriptase inhibitors are recommended as an alternative regimen for HIV-infected patients undergoing tuberculosis treatment in resource-limited settings. Few data exist on the efficacy of such regimens in tuberculosis patients. In 34 tuberculosis/HIV-co-infected patients treated with zidovudine/lamivudine/abacavir, 76% achieved HIV RNA less than 50 copies/ml at 24 weeks. No cases of hypersensitivity or immune reconstitution syndrome were observed. These data support the continuing evaluation of nucleoside-based antiretroviral regimens as an alternative treatment for this population.

Topics: Adult; Antitubercular Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Neutropenia; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Tuberculosis, Pulmonary; Zidovudine

Topics: Dideoxynucleosides; Drug Hypersensitivity; Female; Fibrin; HIV Infections; Humans; Lung; Middle Aged; Pneumonia; Reverse Transcriptase Inhibitors

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Spain; Species Specificity; Treatment Failure; Viral Load

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

To investigate predictors of continued HIV RNA viral load suppression in individuals switched to abacavir (ABC), lamivudine (3TC) and zidovudine (ZDV) after successful previous treatment with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy.. An observational cohort study, which included individuals in the Swiss HIV Cohort Study switching to ABC/3TC/ZDV following successful suppression of viral load. The primary endpoint was time to treatment failure defined as the first of the following events: two consecutiveviral load measurements > 400 copies/ml under ABC/3TC/ZDV, one viral load measurement > 400 copies/ml and subsequent discontinuation of ABC/3TC/ZDV within 3 months, AIDS or death.. We included 495 individuals; 47 experienced treatment failure in 1459 person-years of follow-up [rate = 3.22 events/100 person-years; 95% confidence interval (95% CI), 2.30-4.14]. Of all failures, 62% occurred in the first year after switching to ABC/3TC/ZDV. In a Cox regression analysis, treatment failure was independently associated with earlier exposure to nucleoside reverse transcriptase inhibitor (NRTI) mono or dual therapy [hazard ratio (HR), 8.02; 95% CI, 4.19-15.35) and low CD4 cell count at the time of the switch (HR, 0.66; 95% CI, 0.51-0.87 by +100 cells/microl up to 500 cells/microl). In patients without earlier exposure to mono or dual therapy, AIDS prior to switch to simplified maintenance therapy was an additional risk factor.. The failure rate was low in patients with suppressed viral load and switch to ABC/3TC/ZDV treatment. Patients with earlier exposure to mono or dual NRTI therapy, low CD4 cell count at time of switch, or AIDS are at increased risk of treatment failure, limiting the use of ABC/3TC/ZDV in these patient groups.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; Genes, MDR; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Mutation; Prognosis; Proportional Hazards Models; Reverse Transcriptase Inhibitors; RNA, Viral; Switzerland; Treatment Failure; Viral Load; Zidovudine

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Middle Aged

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

Topics: Alleles; Codon; Dideoxynucleosides; Drug Resistance, Viral; HIV; HIV Infections; HLA-B Antigens; Humans; Mutation; Reverse Transcriptase Inhibitors

To analyze the safety and effectiveness of abacavir, lamivudine, and zidovudine (ABC/3TC/ZDV) in antiretroviral therapy (ART)-naive HIV-infected patients.. Retrospective observational cohort study.. We analyzed all consecutive ART-naive HIV-infected patients who initiated ABC/3TC/ZDV in 71 centers throughout Spain and had a clinical visit and laboratory data at least 16 weeks after initiating this regimen. We assessed safety, mortality, new AIDS-defining conditions (ADCs) and treatment failure, the latter defined by any of the following: (1) reduction in plasma HIV-1 viral load (pVL) <1 log during the first 12 weeks of ART, unless it was less than the lower limit of quantification (LOQ); (2) failure to achieve a pVL or = LOQ after achieving a pVL

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Hypersensitivity; Lamivudine; Male; Patient Compliance; Retrospective Studies; Spain; Treatment Failure; Zidovudine

To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition.. The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily.. Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30-36 weeks of gestation) and again postpartum (6-12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography.. Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration-time curve (AUC) of 5.9 mg.h/l [90% confidence interval (CI), 5.2-6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6-2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91-1.18) and 0.79 (90% CI, 0.65-0.98), respectively.. Abacavir AUC during pregnancy was similar to that at 6-12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg.h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Chromatography, High Pressure Liquid; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies

Topics: Acute Disease; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Male; Middle Aged; Respiratory Hypersensitivity; Reverse Transcriptase Inhibitors

HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTI)-only based, comprising tenofovir DF(TDF) have been shown to lead to high rates of virological failures (VF), mainly in patients on first-line combination therapy. We wished to investigate the virological response to these regimens in a large cohort of antiretroviral (ARV)-treated patients.. Patients followed-up in the Aquitaine Cohort in 2001-2003 and who had received NRTI-based, TDF-including regimens for at least 3 months were included. The VF was defined as: (i) a decrease in plasma HIV-1 RNA <0.5 log(10)copies/ml between M0 and M3; or (ii) a plasma HIV-1 RNA >50 copies/ml at M3 in patients with plasma HIV-1 RNA <50 copies/ml at M0. The baseline RT genotype was determined in a subgroup of patients.. Within 121 patients (95% ARV-experienced) who received either lamivudine (3TC)/didanosine (DDI)/TDF (n=48), or abacavir (ABC)/3TC/TDF (n=14), or 3TC/zidovudine (ZDV)/TDF (n=27), or 3TC/ZDV/ABC/TDF (n=20), or DDI/ABC/TDF (n=12), the ABC/3TC/TDF and DDI/ABC/TDF combinations were associated with the highest frequencies of VF. In contrast the use of ZDV was related to a better virological response. The baseline RT genotype was also predictive of the virological outcome.. NRTI-based, TDF-including therapies can lead to high rates of VF both in ARV-naïve and in ARV-experienced patients. Our data strongly suggest the interest of associating ZDV and TDF in these regimens.

Topics: Adenine; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; France; HIV Infections; HIV Reverse Transcriptase; HIV-1; Hospitals, University; Humans; Lamivudine; Mutation; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Species Specificity; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

Topics: Anti-HIV Agents; Anxiety; Child; Depression; Dideoxynucleosides; Headache; HIV Infections; HIV-1; Humans; Male; Mental Disorders; Reverse Transcriptase Inhibitors; Sleep Wake Disorders

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Organophosphonates; Pilot Projects; Randomized Controlled Trials as Topic; Tenofovir

Data on adherence to and acceptability of once daily lamivudine and abacavir are few.. Twenty-four U.K. human immunodeficiency virus type-1 infected children 2-13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open label pharmacokinetic study of twice (every 12 hours) versus once (every 24 hours) daily lamivudine and abacavir. Caregivers were asked to complete an adherence questionnaire at screening, week 0 (switch once daily to twice daily) and weeks 4, 12 and 24. Acceptability was also assessed at screening and week 24.. Fifteen children were taking lamivudine and abacavir as part of their regimens, 8 lamivudine only and 1 abacavir only. After switching to lamivudine/abacavir every 24 hours, 7 (29%) received once daily regimens for all drugs. Twenty-three (96%) caregivers thought that switching to once daily lamivudine/abacavir would make things a lot/a little easier for their child: 17 (71%) thought it was actually easier after switching. Six mothers with children taking a mixture of twice/once daily drugs changed their mind, whereas all mothers of children on once daily regimens agreed that it was a lot easier. Nonadherence (missing doses in the last 3 days) was reported for 8 of 118 (7%) completed questionnaires; missed doses were reported for every drug in the regimen with reasons such as "not at home," "forgot" or "routine different from normal." However, viral loads in all these children remained <100 copies/mL.. Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Male; Patient Acceptance of Health Care; Patient Compliance; Prospective Studies; Risk Assessment; Sex Factors; Single-Blind Method; Treatment Outcome; United Kingdom; Viral Load

Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.

Topics: Adult; Anti-HIV Agents; Australia; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Incidence; Male; Middle Aged

We analyzed 3,475 human immunodeficiency virus sequences and 241 therapeutic histories. The L74I mutation was carried by 7% of viruses. L74I was strongly associated with T215F, K70R, and V75M/S/T/A mutations and increased with the number of thymidine analog mutations. It seemed to be linked to the use of abacavir or efavirenz.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Oxazines; Reverse Transcriptase Inhibitors; Risk Factors

To evaluate risk factors associated with the abacavir hypersensitivity reaction during primary HIV infection (PHI).. Acute HIV Infection and Early Disease Research Program protocol (AIEDRP) AI-02-001 provided antiretroviral therapy including abacavir. This retrospective analysis evaluated variables potentially associated with hypersensitivity in the cohort enrolled in AI-02-001 at the University of Washington Primary Infection Clinic.. Cases of suspected hypersensitivity were identified prospectively and reviewed retrospectively using a standardized case definition. Controls were the remaining cohort without hypersensitivity. Univariate analyses were performed by linear logistic regression.. Nine (18%) of 50 individuals treated with abacavir developed suspected hypersensitivity. Two of nine cases and no controls were HLA-B5701 positive. When antiretroviral medications were started, cases had lower mean CD8 T-cell percentage and plasma HIV RNA value. After 2 weeks on abacavir, cases had a lower mean HIV RNA value and a trend towards greater decrease in RNA. Cases began abacavir a median of 103 days after HIV acquisition compared to 48 days for controls. There was no significant in vitro abacavir-specific lymphoproliferation or IFN-gamma production in peripheral blood mononuclear cells from individuals following the suspected hypersensitivity reaction.. Abacavir use during PHI may be associated with increased risk of hypersensitivity. As in chronic infection, HLA-B5701 is associated with the abacavir hypersensitivity reaction in PHI. Although levels of CD8 T cells and HIV RNA may be risk factors for hypersensitivity, the observed association may be due to correlation with HLA-B5701. The interesting temporal association of hypersensitivity with initiation of abacavir later in PHI merits future investigation.

Topics: Adult; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Flow Cytometry; HIV Infections; HIV-1; HLA-B Antigens; Humans; Logistic Models; Male; Prospective Studies; Retrospective Studies; Risk; Statistics, Nonparametric

Numerous large, long-term clinical trials have assessed the safety and efficacy of the two antiretroviral nucleoside analogs lamivudine and abacavir as components of highly active antiretroviral therapy for the treatment of patients with HIV-1 infection. This analysis pools the safety data on multi-drug regimens containing lamivudine/abacavir in combination with a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or nucleoside reverse transcriptase inhibitor.. Data are presented from 2279 treatment-naive HIV-1-infected patients who were enrolled in one of five clinical trials that assessed the safety and tolerability of lamivudine/abacavir in combination with a third antiretroviral agent. The well characterised combination of lamivudine/zidovudine plus efavirenz was used as the comparator arm. All available safety data (including data beyond 48 weeks) were used in all analyses, which included calculation of treatment emergent laboratory values, adverse events (AEs), serious AEs, fatalities, drug discontinuations and any summaries by study week of safety data.. In the total lamivudine/abacavir group, 1585 of 2229 (71%) patients experienced at least one drug-related AE during the study compared with 247 of 325 (76%) patients in the lamivudine/zidovudine/efavirenz treatment group. The most common drug-related AEs reported during the study were diarrhoea (19%), nausea (18%) and dizziness (12%) in patients treated with lamivudine/abacavir plus a third agent, and nausea (31%), dizziness (27%) and headache (16%) in the comparator group. Overall, in the total lamivudine/abacavir group there were only three severe (Division of AIDS 1992 toxicity table grade 3 or 4) AEs that were reported in >1% of subjects: drug hypersensitivity, elevated ALT levels and elevated AST levels. In the lamivudine/zidovudine/efavirenz group, six severe AEs that occurred in >1% of the safety population were reported. The abacavir hypersensitivity reaction rate reported in these five studies was comparable with the previously reported rate. In addition, there were no patient fatalities attributed by investigators to the study drugs.. This analysis indicates that the combination of lamivudine/abacavir is generally safe for the majority of patients when used as part of combination therapy.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Controlled Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Male; Oxazines; Prospective Studies; Time Factors; Treatment Outcome; Zidovudine

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV; HIV Infections; Humans; Lamivudine; Organophosphonates; RNA, Viral; Tenofovir; Treatment Failure

Treatment simplification in antiretroviral-experienced patients receiving protease inhibitor (PI)-containing antiretroviral regimens seems safe, but randomized trials have limited power to detect differences in virological rebound (VR) between different switch strategies.. From the French Hospital Database on HIV, we selected 2462 patients with undetectable viral load (VL) who switched from a first PI-containing antiretroviral combination (cART) to a combination containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC). Factors associated with VR and with immunological efficacy (gain of > or = 50 CD4(+) cells/microl) were identified by using Cox models.. The 12-month Kaplan-Meier probabilities of VR were 6.8, 13.7 and 12.3% in patients switching to EFV-cART, NVP-cART and ABC-cART, respectively. Factors associated with VR were female sex, younger age, antiretroviral exposure before the first cART, time on first cART, higher VL at first cART initiation, a stavudine/didanosine backbone (rather than zidovudine/lamivudine) after the switch, and a switch to NVP or ABC [respective adjusted hazard ratio versus EFV: 1.53; 95% confidence interval (CI), 1.21-1.94; and 1.53; 95% CI, 1.12-2.08]. When the analyses were restricted to patients who were antiretroviral-naive before their first cART, NVP (but not ABC) was associated with VR. Immunological outcomes did not differ among the three switch regimens.. When VL is undetectable on a first PI-cART regimen, switching to an EFV-containing regimen is more likely to avoid VR than switching to an ABC or NVP-containing regimen. ABC may be an alternative to EFV for patients who were not exposed to antiretroviral before their first cART regimen, after checking for ABC resistance mutations.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nevirapine; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Outcome; Viral Load

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Topics: Child; Dideoxynucleosides; Drug Approval; Drugs, Generic; HIV Infections; Humans; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Previous studies have described the presence of the L74V reverse transcriptase (RT) mutation in highly experienced individuals as a risk factor for reduced response to tenofovir and selection of the K65R mutation. This study examined whether, in the context of a first-line abacavir/lamivudine highly active antiretroviral therapy (HAART) regimen, K65R might occur as a minority population where L74V was detected at virological failure.. Four previously ART-naive individuals undergoing virological failure were selected, all receiving abacavir and lamivudine with either protease inhibitors or efavirenz and with virus displaying L74V and M184V or M184V alone following transient L74V emergence. Clonal analyses from plasma viral RNA were performed on samples taken at baseline and after virological failure. Clones were screened for the presence of K65R by real time K65R-selective PCR (K65R-sPCR). RT genes from clones displaying K65R were sequenced.. At baseline, all clones were wild type at codon 65 by K65R-sPCR, except in one patient in which one of 720 clones exhibited K65R. At failure with M184V and L74V present by bulk sequencing, this K65R was retained in one of 855 clones assessed. One additional patient (M 184V alone by bulk sequencing) displayed K65R in one of 466 failure clones. Virological failure samples from the remaining two patients were wild type at codon 65 in all of 524 and 270 clones, respectively.. Minority species harbouring K65R are uncommon and occur at very low population densities in patients experiencing virological failure on first-line abacavir/lamivudine-containing HAART.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure; Viral Load

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.015-5 mg/l for all five NRTIs. The average accuracies for the assay were 92-102%, inter- and intra-day coefficients of variation (CV) were <2.5% and extraction recoveries were higher than 97%. This method proved to be simple, accurate and precise, and is currently in use in our laboratory for the quantitative analysis of NRTIs in plasma.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Didanosine; Dideoxynucleosides; Drug Stability; HIV; HIV Infections; Humans; Lamivudine; Quality Control; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Stavudine; Zidovudine

The purpose of this study was to compare treatment satisfaction with triple nucleoside reverse transcriptase inhibitor (NRTI) highly active antiretroviral treatment (HAART) regimens including abacavir (ABC) to HAART regimens that include protease inhibitors (PIs) and to estimate the relationship between patient satisfaction and adherence to HAART. Three open-label clinical trials comparing ABC-including HAART regimens with PI-including HAART regimens were completed, two with patients previously untreated with antiretroviral therapy and one with patients successfully treated with PI-including HAART regimens. The HIV Treatment Satisfaction Questionnaire (HIVTSQ) was completed at several time points during each trial. Levels of patient satisfaction with the ABC and PI regimens were compared for all three trials. The correlation between adherence and patient satisfaction scores was measured using data from an adherence questionnaire in one of the studies. In all three clinical trials, patient satisfaction scores were significantly higher with an ABC-including triple NRTI HAART regimen than with a PI-including HAART regimen. The difference was apparent by week 4 of the trial and was maintained throughout the trial time period. Inspection of the item responses in the patient satisfaction questionnaire indicated that treatment convenience, flexibility, impact on lifestyle, and side effects were key factors in the difference in satisfaction between the treatment groups. In addition, patient satisfaction was shown to be significantly correlated with adherence defined as taking 95% or more of prescribed doses. Greater satisfaction was reported by patients given an ABC-including HAART regimen than those given a PI-including HAART regimen. Patient satisfaction may be an indicator for better treatment adherence.

Topics: Adult; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Dideoxynucleosides; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Logistic Models; Male; Multivariate Analysis; Patient Compliance; Patient Satisfaction; Risk Assessment; Severity of Illness Index; Survival Analysis; Treatment Outcome; Viral Load

To study the possible influence of patient characteristics on abacavir pharmacokinetics.. A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM.. Abacavir pharmacokinetics was well described by a two-compartment open model with linear absorption and elimination. Typical population estimates for the absorption rate constant (Ka), the apparent central distribution volume (Vc/F), the apparent peripheral distribution volume (Vp/F), the apparent intercompartmental clearance (Q/F) and the apparent plasma clearance (CL/F) were 1.8 h(-1), 75 l, 23.6 l, 10 l h(-1) and 47.5 l h(-1), respectively. Apparent plasma clearance was positively related to bodyweight. Individual Bayesian estimates of CL/F were used to calculate abacavir AUC. The latter decreased from 10.7 +/- 5.0 to 5.7 +/- 1.6 mgh l(-1) when bodyweight increased from 36 to 102 kg. This drop in abacavir exposure could lead to suboptimal treatment for the heaviest patients, as antiviral efficacy of abacavir is known to be related to its AUC. A 400 mg abacavir dose would be necessary to achieve adequate exposure to abacavir in patients weighing more than 60 kg.. The apparent plasma clearance of abacavir was positively related to bodyweight. The efficacy of the current recommended abacavir dosage for patients with high bodyweight should be evaluated in further studies.

Topics: Administration, Oral; Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; Tablets

Abacavir pharmacokinetics was studied in 105 children by a population approach performed with NONMEM. A 1-compartment open model with linear absorption and elimination adequately described the data. Typical population estimates (percent interindividual variability) of absorption rate constant, apparent distribution volume, and apparent plasma clearance were 1.79 h(-1) (58%), 42.9 L (53%), and 24.3 L/h (30%), respectively. Apparent plasma clearance was positively related to body weight. Individual Bayesian estimates of apparent plasma clearance were used to calculate individual abacavir area under the concentration curve (AUC). For the current weight-based regimen, abacavir exposure was found to be constant throughout the age range of the study, with an overall mean AUC value of 8.5 +/- 2.5 mg x h/L, which is slightly greater than the mean AUC value reported in adults. This study confirms the relevance of the current weight-based abacavir dosage regimen in pediatric patients.

Topics: Adolescent; Age Distribution; Anti-HIV Agents; Area Under Curve; Body Weight; Child; Child, Preschool; Dideoxynucleosides; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Male; Metabolic Clearance Rate; Models, Biological; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

The human immunodeficiency virus type 1 (HIV-1) resistance profile, K65R, K70E and M184V, on reverse transcriptase gene was associated with the virologic rebound consecutively to the switch of lopinavir/r to tenofovir DF in a stable regimen with nucleoside backbone of abacavir, lamivudine and didanosine. The high selective pressure on the same resistance pathway was probably associated with the loss of antiviral potency, even in well-controlled patient.

Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Gabon; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lopinavir; Microbial Sensitivity Tests; Mutation; Organophosphonates; Pyrimidinones; Tenofovir; Viral Load

Lipoatrophy is an important manifestation of the lipodystrophy syndrome and is particularly associated with stavudine exposure. Increased apoptosis has been suggested as a possible mechanism of lipoatrophy. We assessed the degree and reversibility of adipocyte apoptosis in patients with lipoatrophy before and 48 weeks after substituting abacavir or zidovudine for stavudine.. Apoptotic adipocytes were identified using terminal transferase dUTP nick end labeling and quantified using video image analysis.. Fat biopsy specimens were obtained from patients before (n = 15) and 48 weeks after (n = 10) switching from stavudine and from 20 HIV-uninfected controls. More apoptotic cells were seen in fat samples from patients with lipoatrophy treated with stavudine than in specimens from controls (P < 0.0001). Forty-eight weeks after switching from stavudine to abacavir or zidovudine, there was a reduction in apoptotic cells per unit area (P = 0.01) and as a proportion of all adipocytes present (P = 0.02) in patient biopsy specimens. Levels of adipocyte apoptosis in the 48-week biopsy specimens were no longer significantly different from those seen in control biopsy specimens (P > 0.1).. Increased apoptosis is present in fat samples from patients with lipoatrophy treated with stavudine. This improves toward normal within 48 weeks of switching from stavudine to abacavir or zidovudine, suggesting a causative role for stavudine in this process.

Topics: Adipocytes; Adipose Tissue; Adult; Anti-HIV Agents; Apoptosis; Biopsy; Dideoxynucleosides; DNA; DNA Fragmentation; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; In Situ Nick-End Labeling; Male; Middle Aged; Stavudine; Zidovudine

Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men.. Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as > or =1 log10 copies/mL across the visit pairs.. : Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with < or =1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for < or =7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts.. Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.

Topics: Adult; Age Factors; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Depression; Dideoxynucleosides; Ethnicity; HIV; HIV Infections; Humans; Logistic Models; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; RNA, Viral; Treatment Refusal

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Labeling; HIV Infections; Humans; Liver Diseases

Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice.. We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI).. 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008).. In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Topics: Adult; Anti-Retroviral Agents; Cohort Studies; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Mutation; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Time Factors; Viral Load

Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by >/= 2 log(10) by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log(10); [range, 7650->750,000]) and 277 cells/mm(3) (range, 59-598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders (virologic success). Twelve patients (63%) were considered nonresponders and/or with virologic failure. The study was prematurely interrupted because of a high rate of treatment failure. Resistance testing available for 11 nonresponders (58%) showed: 2 patients with wild-type, 5 patients with M184V (reducing susceptibility to 3TC and ABC), 4 patients with M184V+K65R (K65R is responsible for reducing susceptibility to ABC, 3TC and TDF), and none with K65R alone. In conclusion, the combination of ABC, 3TC and TDF cannot be recommended for the initial regimen in HIV treatment-naive patients.

Topics: Adenine; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Organophosphonates; Pilot Projects; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure; Viral Load

To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy.. A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response.. The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002).. A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Stavudine; Stevens-Johnson Syndrome

Topics: Adenine; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load; Zidovudine

The clinical treatment of patients with HIV and adverse drug events may be enhanced by an understanding of the underlying mechanisms. About 4% of patients with HIV receiving the potent antiretroviral drug abacavir develop a hypersensitivity reaction. This idiosyncratic reaction appears to have an immunologic component that has yet to be defined. Given that the T-cell type 2 cytokine IL-4 may be overproduced by patients with allergy or other immunologic dysregulation, an index cytokine profile could help elucidate the character of a drug-specific hypersensitivity reaction.. Quantitation of the production of the type 2 IL-4 and the counterregulatory type 1 cytokine IFN-gamma in patients with abacavir-related hypersensitivity.. Intracellular cytokines were enumerated in blood T cells by flow cytometry. Subjects were grouped for evaluation as patients with a hypersensitive response after abacavir treatment, patients initiating abacavir who also were evaluated again after 1 month on abacavir, patients on abacavir for 6 months without hypersensitivity, and HIV-naive control individuals.. There was a significant association between increased IL-4 production by CD4 and CD8 T lymphocytes and hypersensitivity reactions to abacavir. Lymphocytes from hypersensitive subjects expressed CD28 and the anti-HIV chemokine macrophage inflammatory protein 1beta with a frequency comparable with HIV-naive control cells, suggesting the possibility that the activated T cells from patients with hypersensitivity are functional.. The expansion of type 0 and type 2 T cells phenotyped by IL-4 production may correlate with abacavir-associated hypersensitivity. The data suggest a cytokine bias that may facilitate B-cell differentiation and downregulate T-cell cytotoxic responses.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Therapy, Combination; Flow Cytometry; HIV Infections; HIV-1; Humans; Hypersensitivity; Interferon-gamma; Interleukin-4; Leukocytes, Mononuclear; Lymphocyte Count

Topics: Acidosis, Lactic; Adenine; Anti-HIV Agents; Dideoxynucleosides; Fatal Outcome; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Tenofovir

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

Simplification of combined antiretroviral therapy in HIV-infected patients is possible, but virological success can be compromised by the development or emergence of resistant viruses.. Worsening renal functioning in a patient under successful combination antiretroviral therapy resulted led to the replacement of indinavir by abacavir. Eight weeks later, his viral load rose and he developed a mutant virus resistant to all the nucleoside analogs.. Our case report illustrates the danger of streamlining combined antiretroviral therapy composed only of nucleoside analogs in patients already successfully treated with nucleoside analogs, by exposing them to the risk of the emergence of a mutant virus.

Topics: Aged; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Male; Mutation; Viral Load

Topics: Anti-HIV Agents; Clofibric Acid; Dideoxynucleosides; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Fibric Acids; HIV Infections; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Rhabdomyolysis

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Organophosphonates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure

Based on the short-term results of the AIDS Clinical Trials Group (ACTG) A5095 trial, zidovudine (ZDV)/lamivudine (3TC)/abacavir (ABC) is no longer recommended as a first-line antiretroviral regimen. Data on the efficacy of this triple nucleoside reverse transcriptase inhibitor (NRTI) combination compared with the gold-standard nonnucleoside reverse transcriptase inhibitor (NNRTI) regimen could provide important information.. Patients were selected from three prospective cohorts of patients who received first-line therapy with ZDV/3TC plus an NNRTI or ABC, started after January 1998. Immunovirological changes and the proportion of treatment discontinuations were compared between groups.. Of the 380 patients, 190 started on ABC [the triple-NRTI group (3N)] and 190 on NNRTI. At baseline, there was no statistical difference between the NNRTI and 3N groups for age (mean=38 years), sex (66% male) or CD4 cell count (mean=305 cells/muL). Mean baseline plasma HIV-1 viral load (pVL) was higher in the 3N group (4.6 vs. 4.3 log10 HIV-1 RNA copies/mL: P<0.01). Lower and higher estimates of median pVL decrease at month 24 were 2.05 and 4.76 log10 copies/mL in the 3N group, and 1.73 and 4.31 log10 copies/mL in the NNRTI group (not significant). CD4 cell count evolution did not differ between groups. Treatment discontinuation occurred in 45% vs. 44% of patients in the NNRTI and 3N groups, respectively, after median durations of 9 and 4 months, respectively (P=0.02).. In this prospective cohort, 3N and NNRTI regimens as first-line therapy produced similar immunovirological responses.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; Treatment Failure; Treatment Outcome; Viral Load; Zidovudine

Once highly active antiretroviral therapy (HAART) fails to suppress HIV replication and resistant viruses emerge, it is difficult to find a salvage regimen since cross-resistance is high among the available classes of antiretroviral drugs. In this retrospective analysis, genotypic resistance profiles were analysed in 24 patients who switched treatment to abacavir (ABV), efavirenz (EFV), and either a NRTI or a PI at baseline and after 24 weeks of treatment. At baseline, 71% of patients harboured at least one resistance mutation in the protease gene. In the RT gene, 87.5% of the patients showed nucleoside analogue resistance mutations, and an equal 87.5% showed resistance mutations to non-nucleoside analogues. After 24 weeks of treatment, only mutations to nucleoside analogues raised in 95.8% of the patients, while resistance mutations to the other drug classes remained constant. Substitutions conferring cross-resistance within each drug family were very common among this treatment-experienced population. These data also indicate that salvage therapy is likely to remain one of the most important issues in the treatment of HIV infections.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Oxazines; Salvage Therapy; Time Factors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Treatment Refusal; Zidovudine

Resistance to antiretroviral drugs in human immunodeficiency virus (HIV) disease may be discordant between blood and cerebrospinal fluid (CSF). However, there is no method by which patients who are likely to harbor resistant HIV in the CSF can be noninvasively identified. Activated monocytes are known to traffic through the brain and perivascular microglia are considered to "turnover" regularly from bone marrow-derived monocytes. Monocytes lack certain kinases necessary to metabolize some antiretroviral drugs, making it possible that monocytes, could deliver antiretroviral drugs to the brain. Low monocyte counts in the peripheral blood, however, would be expected to lead to decreased trafficking and turnover of monocytes, with less drug delivery to the brain. The authors hypothesized that this would increase the likelihood of drug resistant HIV in the central nervous system. To test this, 24 matching CSF and plasma samples that had been prospectively collected and stored from patients treated with nucleoside analogue reverse transcriptase inhibitor drugs were assessed for genotypic resistance. Those CSFs, with evidence of resistance mutations, were compared to those without for peripheral blood monocyte count, hemoglobin, CD4 cell count, and zidovudine (ZDV) use. The same analyses were repeated on the plasma samples. There were 11 CSFs with evidence of resistance mutations. The peripheral blood monocyte count was significantly lower in the CSF resistant group (0.29 +/- 0.16) versus (0.52 +/- 0.21) x 10(9)/L (P <.001). There was no difference between the groups according to hemoglobin, CD4 cell count, total white cell count, or use of ZDV. There was no difference between resistant and sensitive plasma samples according to peripheral blood monocyte count. To further test the hypothesis, the authors determined the concentrations of ZDV, stavudine, and abacavir in monocytes after each drug had been added to monocyte cultures. There was a significant decline in the concentration of each drug in the supernatant, implying that it had been "taken up" by the monocytes. These preliminary data suggest that peripheral blood monocytes may be important in delivery of antiretroviral drugs to the brain and the development of resistance.

Topics: Anti-HIV Agents; Biomarkers; Buffers; Culture Media; Dideoxynucleosides; Drug Resistance, Viral; HIV; HIV Infections; Humans; In Vitro Techniques; Leukocyte Count; Monocytes; Stavudine; Zidovudine

A 42-year-old man with human immunodeficiency virus (HIV) infection and a history of complex partial seizures developed severe anemia after the addition of valproic acid to his stable antiretroviral regimen of zidovudine, lamivudine, and abacavir. The inhibition of zidovudine glucuronidation by valproic acid and the resultant zidovudine hematologic toxicity is the proposed mechanism of the interaction.

Topics: Anemia; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Interactions; Epilepsy, Complex Partial; HIV Infections; Humans; Lamivudine; Male; Valproic Acid; Zidovudine

Topics: Adenine; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Nucleosides; Nucleotides; Organophosphonates; Organophosphorus Compounds; Prevalence; Tenofovir

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; European Union; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Patient Selection; Pilot Projects; Safety; Tenofovir; Treatment Failure; Viral Load

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Male; Middle Aged

Although the ever-expanding armamentarium of antiretroviral drugs has significantly decreased the morbidity and mortality due to human immunodeficiency virus infection, patients and clinicians are increasingly faced with the problems of inadequate or toxic response to therapy that may be genetically mediated. Significant evidence now exists that interindividual differences, such as efficacy of therapy, hypersensitivity reactions, and metabolic complications as a result of antiretroviral therapy, are in part genetically determined. This article reviews the significant studies published to date in the area of the pharmacogenetics of antiretroviral therapy and summarizes current trends, as well as areas where further research is needed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; Haplotypes; HIV Infections; HLA Antigens; Humans; Hyperbilirubinemia; Pharmacogenetics; Receptors, Chemokine

Abacavir, a human immunodeficiency virus-1 (HIV-1) nucleoside-analogue reverse transcriptase inhibitor, causes severe hypersensitivity in 4-8% of patients. HLA B*5701 is a known genetic risk factor for abacavir hypersensitivity in Caucasians. Our aim was to confirm the presence of this genetic factor in our patients, and to determine whether genotyping for HLA B*5701 would be a cost-effective use of healthcare resources.. Patients with and without abacavir hypersensitivity were identified from a UK HIV clinic. Patients were genotyped for HLA B*5701, and pooled data used for calculation of test characteristics. The cost-effectiveness analysis incorporated the cost of testing, cost of treating abacavir hypersensitivity, and the cost and selection of alternative antiretroviral regimens. A probabilistic decision analytic model (comparing testing versus no testing) was formulated and Monte Carlo simulations performed.. Of the abacavir hypersensitive patients, six (46%) were HLA B*5701 positive, compared to five (10%) of the non-hypersensitive patients (odds ratio 7.9 [95% confidence intervals 1.5-41.4], P = 0.006). Pooling of our data on HLA B*5701 with published data resulted in a pooled odds ratio of 29 (95% CI 6.4-132.3; P < 0.0001). The cost-effectiveness model demonstrated that depending on the choice of comparator, routine testing for HLA B*5701 ranged from being a dominant strategy (less expensive and more beneficial than not testing) to an incremental cost-effectiveness ratio (versus no testing) of Euro 22,811 per hypersensitivity reaction avoided.. Abacavir hypersensitivity is associated with HLA B*5701, and pre-prescription pharmacogenetic testing for this appears to be a cost-effective use of healthcare resources.

Topics: Adult; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Monte Carlo Method; Odds Ratio; Pharmacogenetics; Point-of-Care Systems; Reverse Transcriptase Inhibitors; Risk Factors

We have previously described an in vitro model for the evaluation of the effects of different immunomodulatory agents and immunotoxins (ITs) on cells latently infected with human immunodeficiency virus (HIV). We demonstrated that latently infected, replication-competent cells can be generated in vitro after eliminating CD25+ cells with an IT. Thus, by selectively killing the productively infected cells with an anti-CD25 IT we can generate a population of latently infected cells. CD25- cells generated in this manner were treated with nucleoside analog reverse transcriptase inhibitors and subsequently activated with phytohemagglutinin in the presence of the drugs. The antiviral activities of zidovudine (ZDV), lamivudine (3TC), and abacavir (ABC) were evaluated by using this model. 3TC and ABC demonstrated significant activity in decreasing HIV production from recently infected resting cells following their activation, whereas the effect of ZDV was more modest. These results suggest that the differences in antiviral activity of nucleoside analogs on resting cells should be considered when designing drug combinations for the treatment of HIV infection. The model presented here offers a convenient alternative for evaluating the mechanism of action of new antiretroviral agents (J. Saavedra, C. Johnson, J. Koester, M. St. Claire, E. Vitteta, O. Ramilo, 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. I-59, 1997).

Topics: Anti-HIV Agents; Cells, Cultured; Dideoxynucleosides; Drug Evaluation, Preclinical; HIV Core Protein p24; HIV Infections; Humans; Immunotoxins; Lamivudine; Phytohemagglutinins; Receptors, Interleukin-2; Reverse Transcriptase Inhibitors; Zidovudine

To analyse the impact of the M184I/V mutation and individual thymidine-associated mutations (TAM) on nucleoside reverse transcriptase inhibitor (NRTI) phenotypic susceptibility and compare these results with those obtained using commercial and public algorithms.. An HIV genotypic/phenotypic database with over 27 000 samples was used to obtain the median fold change (5-95th percentile) in NRTI phenotypic susceptibility for viruses from patients containing individual TAM with or without the M184I or V mutation and for wild-type patient viruses.. The resulting data indicated that in vitro, individual TAM do not have an equivalent impact on NRTI resistance, with some individual TAM having little or no impact on NRTI resistance (e.g. M41L or K219Q/E/H/R). In the presence of the M184I/V mutation, re-sensitization to some drugs, including zidovudine, stavudine and tenofovir was observed despite the presence of a TAM. For didanosine and abacavir, the presence of the M184V mutation and a single TAM did not result in a fold-change increase associated with decreased drug susceptibility. Analysis of public and commercial algorithms revealed a lack of concordance regarding the impact of these mutations, and with the observed phenotypic data.. These analyses should assist in the creation of rules for genotypic drug resistance algorithms for a better reflection of the impact of individual TAM and also the impact of M184I/V on resistance. These data provide additional evidence that retaining lamivudine in those treatment regimens in which TAM can be selected may provide some therapeutic benefit by maintaining the M184V mutation.

Topics: Adenine; Algorithms; Anti-HIV Agents; Databases, Genetic; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; HIV; HIV Infections; Humans; Mutation; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Thymidine; Zalcitabine; Zidovudine

Topics: Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Oxazines; Research Design; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Topics: Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Oxazines; Patient Compliance; Reverse Transcriptase Inhibitors; Zidovudine

It is currently unclear whether the tendency for viral rebound in patients with viral load < 50 copies/ml differs according to the specific drug regimen being used.. To follow 2120 patients in EuroSIDA who had attained < 50 copies/ml on highly active antiretroviral therapy (HAART), without previously virologically failing HAART.. The rate of viral rebound (two consecutive values > 400 copies/ml) was 4.9/100 person-years [95% confidence interval (CI), 4.0-5.8] for patients who were naive pre-HAART and 8.0/100 person-years (95% CI, 7.0-9.0) for those who were experienced with nucleoside analogue reverse transcriptase inhibitors (NRTI) pre-HAART. The rate of rebound was significantly higher in those taking nelfinavir than in those taking efavirenz, both in patients who were naive pre-HAART and those who were NRTI experienced [adjusted rate ratios, 2.83 (95% CI, 1.51-5.31) and 2.86 (95% CI, 1.65-5.00), respectively]. Among patients who were naive pre-HAART, those on abacavir had no evidence of a raised risk of viral rebound (adjusted rate ratio 1.17; 95% CI, 0.51-2.69), but in those with pre-HAART NRTI experience the rate was markedly raised (adjusted rate ratio, 4.48; 95% CI, 2.51-8.00). A similar picture was seen when comparing those on nevirapine with those on efavirenz, although the elevated rate ratio in pre-HAART experienced patients was of lower magnitude (adjusted rate ratio, 1.93). There was no strong evidence that rebound rates differed significantly for any NRTI pairs compared with zidovudine/lamivudine.. Viral rebound rates in patients who have attained < 50 copies/ml appear to differ according to the specific drugs being used.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Nelfinavir; Nevirapine; Oxazines; Prospective Studies; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; Hepatitis C, Chronic; HIV Infections; Humans; Lamivudine; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; Sweet Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

Drug resistance testing provides useful information for managing HIV-infected patients. Phenotyping could add complementary information to genotyping and occasionally be more useful, although is less available to clinicians. Large paired geno-pheno databases have allowed the prediction of phenotypes from genotypes. However, the accuracy of these virtual phenotypes (vPT) in a clinical setting has not been well assessed yet. We analyzed the concordance between vPT and interpreted genotype (GT) in 105 samples belonging to treatment-experienced HIV-infected patients. A high concordance was seen when examining both non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) (r = 0.95 either), while it was lower for nucleoside analogs (r = 0.79). The drugs with lower concordance were abacavir (71.1%), tenofovir (71.5%) and didanosine (71.9%). In 20% of specimens (21/105), the vPT did not provide results for all approved drugs. These were mainly samples with a high number of drug resistance mutations or rare genotypes, which seem to be underepresented in the VircoNET database. Overall, there is good correlation between vPT/GT, especially for PI and NNRTI. The inclusion of additional sequences in the VircoNET database, mainly those derived from heavily treatment-experienced patients and/or from patients failing the most recently approved drugs might improve its performance.

Topics: Adenine; Amino Acid Substitution; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Nucleosides; Organophosphonates; Phenotype; Protease Inhibitors; Reverse Transcriptase Inhibitors; Tenofovir

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Multicenter Studies as Topic; Oxazines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load

To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort.. A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data.. The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65-4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/microl (IQR: 67-305 cells/microl). Our patients were pre-exposed to a median of seven antiretrovirals (2-12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0-8). Overall, the Kaplan-Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45-1.24]. The VL in those patients (n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15-0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05).. Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.

Topics: Adult; Algorithms; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV-1; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; Treatment Failure

Topics: Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Retrospective Studies; Risk Factors

Abacavir (ABC) selects for four mutations (K65R, L74V, Y115F and M184V) in HIV-1 reverse transcriptase (RT), both in vitro and during monotherapy in vivo. The aim of this analysis was to compare the selection of these and other nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations by ABC-containing therapies in the presence and absence of concurrent lamivudine (3TC) and/or zidovudine (ZDV) and to assess the effect of these mutations on phenotypic susceptibility to the NRTIs.. This study was a retrospective analysis of the patterns of NRTI-associated mutations selected following virological failure in six multicentre trials conducted during the development of ABC.. Virological failure was defined as confirmed vRNA above 400 HIV-1 RNA copies/mL. RT genotype and phenotype were determined using standard methods.. K65R was selected infrequently by ABC-containing regimens in the absence of ZDV (13 of 127 patients), while L74V/I was selected more frequently (51 of 127 patients). Selection of both K65R and L74V/I was significantly reduced by co-administration of ZDV with ABC (one of 86 and two of 86 patients, respectively). Y115F was uncommon in the absence (seven of 127 patients) or presence (four of 86 patients) of ZDV. M184V was the most frequently selected mutation by ABC alone (24 of 70 patients) and by ABC plus 3TC (48 of 70 patients). Thymidine analogue mutations were associated with ZDV use. The K65R mutation conferred the broadest phenotypic cross-resistance of the mutations studied.. The resistance pathway selected upon virological failure of ABC-containing regimens is significantly altered by concurrent ZDV use, but not by concurrent 3TC use. These data may have important implications for the efficacy of subsequent lines of NRTI therapies.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Genes, Viral; HIV Infections; HIV-1; Humans; Lamivudine; Mutation; Phenotype; Point Mutation; Retrospective Studies; Reverse Transcriptase Inhibitors; Zidovudine

Topics: Adenine; Adult; Diabetic Nephropathies; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Time Factors; Treatment Failure; Zidovudine

Topics: Adult; Anti-HIV Agents; Depressive Disorder; Dideoxynucleosides; Fatigue; Headache; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Night Terrors

To analyze the influence on adherence and clinical outcome of the replacement of a previous antiretroviral therapy to a simplified approach using zidovudine, lamivudine, and abacavir (Trizivir) and to assess its economic impact.. A retrospective study of 75 pretreated, HIV-infected adult patients who received Trizivir from May 2001 to December 2002. Adherence was assessed by dispensation records or medication counting, CD4 lymphocyte counts, and viral load before and six months after medication change was analyzed; finally, the cost of each therapy was assessed in order to calculate the economic impact of medication change.. Mean adherence significantly increased a 2.5% after medication change; 16 more patients reached optimal adherence, with an NNT (number of patients requiring therapy change in order to obtain one more adherent) of 4.7. The number of patients with undetectable viral load remained almost similar, and mean CD4 cell counts stayed above 500 cells/mm3 in both periods of time. A great variability in incremental costs was seen, due to the varying costs of the previous treatments, and the influence of five intensification therapies using Trizivir. However, when only simplification regimens were analyzed such variability was reduced, and even became favorable in selected cases.. Changing to a simplification therapy using Trizivir resulted in improved adherence, similar clinical outcomes, and a varying economic impact depending on previous antiretroviral therapy costs.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Costs and Cost Analysis; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Patient Compliance; Retrospective Studies; Zidovudine

Stavudine (d4T) has been associated with lipoatrophy and hyperlactatemia. In recent studies, d4T has also been related to both hypercholesterolemia and hypertriglyceridemia. Replacing d4T with another nucleoside analogue such as abacavir (ABC) may reduce lactate levels and improve lipoatrophy in the long term. However, the impact of this strategy on the lipid profile is still unclear. In a prospective and randomized study, fasting lipids were examined over 48 weeks in 112 subjects on d4T regimens, 49 of whom replaced d4T with ABC. The substitution of ABC for d4T was found to be safe and provided a reduction in both LDL cholesterol and the total cholesterol (TC)/HDLc ratio, which might impact favorably on cardiovascular risk.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Lipids; Lipodystrophy; Male; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Stavudine

To describe the immunological and virological outcome, and the factors associated to discontinuation in patients switching to a regimen containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC) after long-term viral suppression under protease inhibitor-including HAART.. Observational study at three outpatient clinics for HIV care in Italy.. Patients with HIV RNA <80 copies/ml and CD4 >200 cells/ml for at least 6 months on a protease inhibitor-containing treatment who switched to NVP, EFV or ABC were included in the study. End-points were immunological failure, virological failure and discontinuation due to toxicity. Survival analyses were performed to find out any independent variables predictive of reaching the end-points.. 177 patients were enrolled; 85 started EFV, 54 NVP and 38 ABC as part of the simplification regimen. 16/159 patients experienced immunological failure: the variables associated to CD4 count decrease were HIV RNA set point value (HR 2.32 for each log10 copies more, P=0.040) and intolerance/toxicity as reason for simplification (HR 3.96, P=0.05). 13/151 subjects showed virological failure; an AIDS diagnosis (HR 6.04, P=0.021) and the use of NVP (HR 7.98, P=0.027) were associated to a worse virological outcome, while patients naive before HAART showed a lower risk of failure (HR 0.008, P=0.007). 16/177 patients discontinued simplification regimen due to toxicity; longer HAART duration before switch was associated to risk reduction (HR 0.92, P=0.004).. Simplification is safe and effective, but it should be offered to patients with shorter treatment duration, and in good clinical and immunovirological conditions.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nevirapine; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

A government clinical trial stopped treatment with abacavir plus AZT plus 3TC, due to more viral rebound than other treatments in the study. Many unknowns remain.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Viral Load; Zidovudine

Without an effective therapeutic human immunodeficiency virus (HIV)-1 vaccine, providing cost-effective, minimally toxic antiretroviral therapy to the many individuals already infected with HIV-1 is a global priority. Implementation of a structured treatment interruption (STI) regimen may be a promising intervention for HIV-1 infection. We adopted this approach out of necessity for 3 severely immunocompromised African children naive to therapy, and increases in the T lymphocyte count and improved quality and sustainability of life 2 years after initiation of the STI regimen were noted.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Dideoxynucleosides; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; HIV Infections; HIV-1; Humans; Lamivudine; Lymphocyte Count; Salvage Therapy; Zidovudine

Differentiation between abacavir hypersensitivity and viral respiratory infections is problematic. Fifteen cases of abacavir hypersensitivity were matched to 30 controls with culture proven influenza A with no abacavir exposure. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction (P < 0.001). Respiratory symptoms (cough, sore throat, or dyspnoea) were not associated with abacavir hypersensitivity (OR = 0.08, P = 0.001). Multivariate analysis confirmed the following associations for abacavir hypersensitivity: the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms. Cough without GI symptoms is associated with influenza.

Topics: Anti-HIV Agents; Case-Control Studies; Cough; Diagnosis, Differential; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Female; Gastrointestinal Diseases; HIV Infections; Humans; Influenza A virus; Influenza, Human; Logistic Models; Male; Multivariate Analysis; Retrospective Studies

To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir.. All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method.. In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score.. We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

Topics: Algorithms; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Multivariate Analysis; Mutation; Reverse Transcriptase Inhibitors; RNA, Viral; Statistics, Nonparametric

To analyze factors associated with long-term (>or=2 years) suppression of virus load (VL), we performed a nested case-control analysis of 1235 Human Immunodeficiency Virus Outpatient Study cohort participants who were well characterized by multiple VL and CD4(+) cell count determinations. Of these patients, 286 (23.1%) had maintained undetectable VLs (i.e., <400 copies/mm(3) or <50 copies/mm(3)) for >or=2 years. Being treatment naive at the start of antiretroviral therapy was associated with a greater likelihood of achieving long-term suppression of VL (odds ratio [OR], 1.5; 95% confidence interval, 1.0-2.0; P=.028). In multivariate models, abacavir, indinavir, efavirenz, and drug combinations that included both lamivudine and indinavir were the most effective treatments for achieving long-term suppression of VL (adjusted OR for each, >3.6; P value for each, <.01). Long-term suppression of VL is more likely in treatment-naive than in treatment-experienced patients, but there were several drugs--abacavir, efavirenz, indinavir, and drug combinations including lamivudine and indinavir--that appeared to be effective, whether they were part of a first or subsequent drug regimen.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Case-Control Studies; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Outpatients; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

To determine incidence of and reasons for discontinuation of abacavir within the first 6 months of therapy.. Retrospective study performed in the cohort of HIV-infected adults who started abacavir in a medical unit between 1997 and December 2000. All adverse drug reactions (ADRs) (especially hypersensitivity) observed in this cohort were reported. The association between drugs and complications were evaluated, using the French method to assess unexpected and toxic drug reactions. According to the variables studied, statistical analysis was performed using the chi2 test, Fisher's exact test, Mann-Whitney, Wilcoxon, or Kruskal-Wallis tests.. All 331 patients treated with abacavir during this time period were included in this study. Early discontinuation of abacavir was observed in 34.1% of patients, the main reasons being adverse effects (20.8%), virologic failure (3.3%), drug holidays (2.7%), poor adherence (2.7%), and death (1.8%). Adverse effects were mostly represented by hypersensitivity reactions. After retrospective analysis, abacavir was stopped for likely hypersensitivity in 8.5% of patients, for doubtful hypersensitivity in 4.2%, and for other adverse effects in 8.1% of patients.. This study shows that abacavir is mainly stopped during the first 6 months of therapy for ADRs. The rate of likely hypersensitivity reaction observed in this study (8.5%) is higher than that observed in clinical trials (5%). After retrospective evaluation, the causality assessment of abacavir is not always certain.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Dideoxynucleosides; Drug Hypersensitivity; Female; France; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors

We investigated risk factors for hypersensitivity reactions (HSR) to abacavir in a case-control study. In a multivariate analysis, white race [odds ratio (OR), 5.16; 95% confidence interval (CI), 1.16-22.97] and a higher CD8 cell count at initiation of abacavir (>850 vs. < or =850 cells: OR, 3.74; 95% CI, 1.19-11.77) were found to be significantly associated with the development of HSR. Age, gender, stage of disease, prior antiretroviral exposure and type of concurrent antiretroviral therapy were not associated with HSR. Differences in predisposition to HSR according to ethnicity and baseline CD8 cell count may be explained by the reported MHC genetic associations with HSR.

Topics: Adult; Anti-HIV Agents; Case-Control Studies; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; Europe; Female; HIV Infections; Humans; Lymphocyte Count; Male; Multivariate Analysis; Odds Ratio; Risk Factors; White People

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Multicenter Studies as Topic; Organophosphonates; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Tenofovir

To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens.. Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity.. Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients.. This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria.

Topics: Acidosis, Lactic; Adult; Alanine Transaminase; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Zidovudine

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Multicenter Studies as Topic; Organophosphonates; Organophosphorus Compounds; Oxazines; Randomized Controlled Trials as Topic; Tenofovir; Treatment Failure

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Hypersensitivity, Delayed; Male; Syndrome

In the first formally presented data on once-daily tenofovir + 3TC + abacavir, the regimen is shown to be suboptimal. Problem is, clinicians have already been using it.

Topics: Adenine; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Pilot Projects; Reverse Transcriptase Inhibitors; Tenofovir

An antiretroviral combination worked much less well than expected in controlling HIV. Patients using all three of these drugs together should talk with their doctor and consider changing treatment.

Topics: Adenine; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Reverse Transcriptase Inhibitors; Tenofovir

Topics: CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; HIV Infections; Humans; Placebos; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Multicenter Studies as Topic; Organophosphonates; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Tenofovir

Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Topics: Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

Topics: Adenine; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Failure

Topics: Adenine; Adult; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Organophosphonates; Tenofovir; Viral Load

Topics: Adult; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Viral Load; Zidovudine

To evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy.. Cross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model.. Patients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated > or = 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlactataemia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactataemia. Choice of thymidine analogue did not influence risk. Hyperlactataemia was associated with acid-base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis.. Screening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid-base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Lactic Acid; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Reproducibility of Results; Risk Factors; Sex Factors; Thymidine

Topics: Adult; Dideoxynucleosides; Disseminated Intravascular Coagulation; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

The K65R mutation in HIV-1 reverse transcriptase is associated with reduced susceptibility to abacavir and tenofovir. We established its prevalence within a large clinical database, and investigated correlations with other resistance-associated mutations and antiretroviral history. The presence of K65R is associated with previous abacavir use. Although rare, it is preferentially selected within non-thymidine analogue-containing regimens, compared with concurrent zidovudine or stavudine use, which is associated with thymidine analogue mutations. Both genetic routes may compromise abacavir and tenofovir activity.

Topics: Adenine; Anti-HIV Agents; Databases, Factual; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Organophosphonates; Organophosphorus Compounds; Prevalence; Reverse Transcriptase Inhibitors; Tenofovir

To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information.

Topics: Adenine; Anti-HIV Agents; Carbamates; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir; Zalcitabine

Topics: Anti-HIV Agents; Biopsy; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Immunohistochemistry; Prospective Studies; Skin Tests

Topics: Adult; Anorexia; Anti-HIV Agents; Anxiety; Central Nervous System; Depression; Dideoxynucleosides; Female; Hallucinations; Hepatitis B; Hepatitis C; HIV Infections; Humans; Mental Disorders; Migraine Disorders; Mood Disorders; Reverse Transcriptase Inhibitors; Sleep Wake Disorders

We report the case of an HIV-infected woman, who presented with chronic and productive cough without sign of hypersensitivity (fever, cutaneous eruption, gastrointestinal disorders), while taking abacavir. All complementary exams being negative, the involvement of abacavir has been suspected. So the drug was stopped leading to a rapid disappearance of cough. It is the first report of chronic cough with abacavir apart of a context of hypersensitivity reaction.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Chronic Disease; Cough; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Middle Aged; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; Rhinitis; Sputum; Stavudine; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oxazines; Practice Patterns, Physicians'; Reverse Transcriptase Inhibitors; Stavudine; Viral Load

Vertigo can cause significant morbidity and make a person unable to perform activities of daily life. A human immunodeficiency virus (HIV)-infected patient experienced vertigo while taking abacavir that resolved immediately on cessation of therapy. The mechanism by which abacavir appeared to be associated with vertigo in this patient is unknown.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Male; Vertigo

HIV patients, understandably, are sometimes unenthusiastic about taking their protease inhibitor (PI) drug therapies because of the numerous pills, the side effects, and chronic problems such as lipodystrophy. To address these problems, researchers have been studying non-PI drug therapies that are potent against HIV. Research has demonstrated successful viral suppression for at least 24 weeks when patients were switched from a PI regimen to an abacavir regimen.

Topics: Dideoxynucleosides; HIV Infections; Humans; Patient Compliance; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

To monitor changes in the numbers of CD8 lymphocytes expressing the activated CD38++ phenotype in peripheral blood samples from patients with primary HIV infection (PHI) treated with highly active antiretroviral therapy (HAART).. Zidovudine, lamivudine, abacavir and amprenavir were initiated during PHI as part of the Quest study. Absolute numbers of CD8+/CD38++ T cells were determined using three-colour flow cytometry, and plasma viral load (VL) was measured using the Roche Amplicor method.. The median, pre-therapy CD8+/CD38++ T cell count was 461/mm(3)(interquartile range 216, 974) in 131 patients compared with normal control values of less than 20 cells/mm(3). Levels fell markedly in parallel with VL within the first 2 weeks of HAART initiation, to a median of 47 cells/mm(3) at 28 weeks (median 436 cell decline; P < 0.001). At that time, 80% of patients had a VL less than 50 copies/ml, and 16.3% of all patients had less than 20 CD8+/CD38++ T cells/mm(3). A continued decrease in CD8+/CD38++ T cell count occurred in 67.2% of patients whose VL was maintained below 50 copies/ml (median change from first to last value -18 cells/mm(3); P < 0.001).. After the initiation of HAART in PHI, CD8+/CD38++ lymphocytes declined rapidly in parallel with VL, and allowed for a normalization of CD8+/CD38++ T cell numbers in a subset of patients at week 28. Cell numbers continued to decline in patients who maintained VL below 50 copies/ml, indicating that the CD8+/CD38++ T cell count may represent a marker of residual viral replication when VL falls below detectable levels after HAART intervention.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Biomarkers; Carbamates; CD48 Antigen; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lymphocyte Count; Male; Middle Aged; Reverse Transcriptase Inhibitors; Sulfonamides; T-Lymphocyte Subsets; Treatment Outcome; Viral Load; Viremia; Zidovudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Haplotypes; HIV Infections; Humans; Major Histocompatibility Complex; Reverse Transcriptase Inhibitors

The use of abacavir--a potent HIV-1 nucleoside-analogue reverse-transcriptase inhibitor--is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1-positive individuals treated with abacavir.. MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (p(c)) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined.. HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29-481], p(c)<0.0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20-268], p(c)<0.0001 ). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43-15 675], p(c)<0.0001). Other MHC markers also present on the 57.1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%.. Genetic susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient.

Topics: Adult; Alleles; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; Genetic Markers; Haplotypes; HIV Infections; HIV-1; HLA-B Antigens; HLA-DQ Antigens; HLA-DR7 Antigen; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA Antigens; Humans; Reverse Transcriptase Inhibitors

Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.

Topics: Adult; Aged; Anti-HIV Agents; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Variation; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Polymorphism, Genetic; Predictive Value of Tests; Racial Groups; Retrospective Studies; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Evaluation; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Patient Dropouts; Retrospective Studies; Reverse Transcriptase Inhibitors; Salvage Therapy; Treatment Failure; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Dideoxynucleosides; Drug Evaluation; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; London; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Viremia; Zidovudine

The treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication.. Thirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144.. At weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL, P = 0.017; week 144: 60 versus 14% with at least one quantifiable pVL, P = 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients.. This proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Follow-Up Studies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load; Virus Replication; Zidovudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Variation; HIV Infections; HLA-B Antigens; Humans; Risk Factors

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Epstein-Barr Virus Infections; Flow Cytometry; Furans; Genotype; HIV Infections; HIV-1; Humans; Immunoglobulin M; Lamivudine; Longitudinal Studies; Male; Proto-Oncogene Proteins c-bcl-2; Receptors, CCR5; Sulfonamides; Time Factors; Zidovudine

Topics: Diabetes Mellitus, Type 2; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Homosexuality, Male; Humans; Hyperglycemia; Male; Middle Aged; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Chemistry, Pharmaceutical; Dideoxynucleosides; Drug Combinations; Drug Labeling; HIV Infections; Humans; Lamivudine; Tablets; Zidovudine

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; HIV Infections; Humans; Quality of Life; Viral Load

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Resistance, Microbial; Furans; HIV; HIV Infections; Humans; Mutation; Sulfonamides

Topics: Didanosine; Dideoxynucleosides; Drug Administration Schedule; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; HIV Infections; Humans; Liver Function Tests; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Carbamates; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; Financing, Government; Furans; HIV Infections; HIV Protease Inhibitors; National Institutes of Health (U.S.); Reverse Transcriptase Inhibitors; Sulfonamides; United States

The male genital tract is considered an anatomical reservoir during therapy for human immunodeficiency virus infection, because the blood-testis barrier may prevent antiretroviral drugs (e.g., the protease inhibitors ritonavir, saquinavir and nelfinavir) from entering the male genital tract. To our knowledge, there are currently no available data on the penetration of the nucleoside analogue abacavir into the male genital tract. Our report shows that abacavir has good penetration into the male genital tract.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; Semen

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Patient Acceptance of Health Care; Patient Compliance; Zidovudine

A simple, reversed-phase HPLC assay has been developed and validated to measure the HIV-1 reverse transcriptase inhibitor abacavir and its two major metabolites, a 5'-glucuronide and a 5'-carboxylate, in human urine and cerebrospinal fluid. Sample preparation involved centrifuging to minimize particulates, then diluting the supernatant before HPLC separation and ultraviolet detection at 295 nm. The method described was used successfully to measure concentrations of abacavir and its two major metabolites in urine and cerebrospinal fluid from HIV-1 infected subjects.

Topics: Chromatography, High Pressure Liquid; Dideoxynucleosides; HIV Infections; Humans; Reproducibility of Results; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

Topics: Aged; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; Humans; Lopinavir; Male; Patient Compliance; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Viral Load

Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y. These viruses all were found to have WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T215). However, differences in fitness among HIV-1(215D), HIV-1(215C), and HIV-1(215S) were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapidly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naive persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy.

Topics: Anti-HIV Agents; Base Sequence; Didanosine; Dideoxynucleosides; DNA, Viral; Drug Resistance, Viral; Evolution, Molecular; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Sequence Data; Mutagenesis; Recombination, Genetic; Reverse Transcriptase Inhibitors; Stavudine; Virus Replication; Zalcitabine; Zidovudine

Hypersensitivity reactions consist of a variable group of clinical findings and have been described for a wide variety of chemical compounds.. This review characterizes the clinical profile of hypersensitivity to the nucleoside reverse transcriptase inhibitor abacavir sulfate.. We performed a retrospective medical review of pooled adverse events data from approximately 200,000 patients who received abacavir in clinical trials, through expanded-access programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction of abacavir therapy.. A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access program and 501 in patients from the post-marketing experience. On review, 176 (9.8%) of these cases were considered definitive and the remainder probable. Based on the 1302 cases identified in clinical trials or the expanded-access program, the calculated incidence of hypersensitivity was 4.3%. Symptoms reported in > or = 20% of cases of this multiorgan reaction included fever, rash, malaise/fatigue, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, among others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%), cough (10%), and pharyngitis (6%). In 90% of cases, hypersensitivity reactions occurred within the first 6 weeks after initiation of abacavir (median time, 11 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within hours of reexposure. Hypotension was present in 25% of these rechallenge reactions. Among patients who received abacavir in clinical trials, the mortality rate was 0.03% (3 per 10,000 patients).. Hypersensitivity to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly by systemic involvement. It can be expected to appear as a treatment-limiting event in approximately 5% of patients. The appearance of clinical symptoms consistent with this syndrome mandates immediate discontinuation of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with any formulation that includes this agent.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Incidence; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Retrospective Studies; Reverse Transcriptase Inhibitors; Survival Rate

Topics: Adult; Agranulocytosis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Fever; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

It has long been known that this drug must never be restarted after it has been discontinued because of a hypersensitivity reaction. Now the manufacturer, Glaxo Wellcome, has warned physicians that serious complications have developed in some cases where the drug had been discontinued for other reasons, but where a hypersensitivity reaction may have occurred without being recognized. The letter, reproduced below, outlines precautions for physicians. Patients who have missed more than one or two doses should always check with their physician before restarting this drug.

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Costs; Drug Therapy, Combination; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine; Zidovudine

Topics: Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Nelfinavir; Nevirapine; Retrospective Studies; Reverse Transcriptase Inhibitors; Stavudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Tablets; Zidovudine

Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Dideoxynucleosides; Furans; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lymph Nodes; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Stavudine; Sulfonamides; Time Factors; Viral Load; Viremia; Zidovudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Mutation; Reverse Transcriptase Inhibitors

In 25 vertically HIV-infected children receiving highly-active antiretroviral therapy, a 3-log10 reduction in plasma HIV RNA load was maintained for 1 year and was associated with a doubling of the CD4-cell percentage. Most (75%) new CD4 cells carried the CD45RA marker of naive cells and there was only a small rise in memory cells (CD45RO). This pattern of immune restoration differs from adults, and may be due to the presence of a functioning thymus in children.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Immunologic Memory; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Male; Nelfinavir; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Zidovudine

Highly active antiretroviral therapy (HAART) may fail, especially in pre-treated patients.. To examine retrospectively whether heavily pre-treated patients not responding to HAART at least once respond to a salvage therapy with abacavir, a nucleoside reverse transcriptase inhibitor (NRTI) plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) and one or two protease inhibitors (PI).. We retrospectively identified and analysed patients followed in the Swiss HIV Cohort Study with > 1000 HIV RNA copies/ml on HAART, naive to abacavir who were switched to abacavir plus one NNRTI (efavirenz or nevirapine) and one or two PI which had not been used in the previous HAART.. Of 23 identified HIV-infected patients with four (median) therapy changes before salvage, 10 patients (43%) achieved a decrease of plasma HIV RNA > 0.5 log10 at 6 months of therapy. After 6 months only two patients had an HIV-1 RNA < 500 copies/ml, one of them < 50 copies/ml. Seven patients increased their CD4 cell counts by > 30% above baseline. Three patients, all with CD4 cell counts < 100 x 10(6)/l before salvage therapy had a > 30% decline in CD4 cell count. An extended number of resistance-associated mutations was found in almost all patients at baseline. One patient had two new AIDS-defining events. Five patients (22%) discontinued treatment because of side-effects, mainly occurrence of a rash.. Salvage therapy in intensively pre-treated patients has a low virological success rate despite usage of abacavir and NNRTI. Nevertheless, this did not correlate with immunological and clinical course. This study emphasizes the difficulty of second-line treatment in HIV-1 infection and stresses the need for new compounds.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Disease Progression; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutation; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Treatment Outcome

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Treatment Outcome; Viral Load

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drug Tolerance; HIV Infections; Humans; Male

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nevirapine; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; Salvage Therapy

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Oxazines; Safety; Salvage Therapy; Treatment Failure

The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Furans; HIV Antibodies; HIV Core Protein p24; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lamivudine; Neutralization Tests; Ritonavir; Sulfonamides; Zidovudine

To investigate the antiviral activity of abacavir added to stable background therapy.. Retrospective analysis.. In 27 subjects with detectable plasma viraemia during stable treatment abacavir was added as the only agent. Patients were pre-treated for 180 weeks (mean) with regimens containing zidovudine (102 weeks) and lamivudine (88 weeks). Results were analysed in two groups: group 1, > 400 HIV RNA copies/ml; group 2, 25-399 copies/ml. In 7/13 group 1 patients genotypic resistance analysis was performed prior to abacavir.. Median follow-up was 28 weeks, median HIV RNA load at baseline 2.48 log10 copies/ml (3.52 and 1.66 log10 copies/ml in groups 1 and 2, respectively). Plasma viraemia was reduced to less than 400 HIV RNA copies/ml in 2/13 subjects in group 1 and 11/11 in group 2 (week 24). Only one patient in group 1 responded transiently to less than 25 HIV RNA copies/ml. In contrast, 10/14 and 11/11 in group 2 reached values below this threshold at weeks 12 and 24, respectively. Overall, 7/13 group 1 patients were found with > or = 2 zidovudine resistance-associated mutations. The lamivudine resistance-associated mutation M184V was present in four of seven cases. All of these patients showed only a moderate and transient reduction of plasma viraemia (medium peak reduction of 0.73 log10 after 20 weeks).. The addition of abacavir during low-level treatment failure may restore or achieve suppression to levels below the cut-off of the ultrasensitive PCR.

Topics: Adult; Aged; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance; Female; Follow-Up Studies; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Failure; Viral Load; Zidovudine

Topics: Anti-Inflammatory Agents; Antiretroviral Therapy, Highly Active; Biopsy; Dideoxynucleosides; HIV Infections; Humans; Kidney; Male; Middle Aged; Nephritis, Interstitial; Prednisolone

To study the development of resistance during 8 weeks of salvage therapy with abacavir and nevirapine in combination with other reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs).. Samples obtained at baseline and after 8 weeks of therapy from 16 heavily pretreated patients were analysed for genotypic and phenotypic resistance. Genotypic resistance was analysed in cell-associated DNA and plasma HIV-RNA using direct sequencing. Phenotypic resistance was analysed in a PBMC-based assay and in a recombinant virus assay. Plasma viral load was measured at baseline and after 2, 4 and 8 weeks of therapy.. The majority of patients was genotypically and phenotypically resistant to lamivudine, abacavir, zidovudine and PIs, whereas 50% of the patients showed resistance to nevirapine at baseline in at least one of the methods used. After 8 weeks of salvage therapy, no additional development of resistance against nucleoside reverse transcriptase inhibitors and PIs could be detected. However, the amount of patients resistant to nevirapine increased to 83%. When the patients were divided into two groups according to baseline resistance against nevirapine, a significantly higher transient reduction in viral load was observed in patients with nevirapine-sensitive HIV at baseline compared to patients with resistant HIV at baseline.. The transient effect of salvage therapy including abacavir and nevirapine was due to the effect of nevirapine. The lack of effect of abacavir was most likely due to cross-resistance between abacavir and lamivudine/zidovudine used in previous treatment.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; DNA, Viral; Drug Resistance, Microbial; Drug Therapy, Combination; Genotype; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Nevirapine; Phenotype; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Salvage Therapy; Viral Load

Topics: Dideoxynucleosides; Drug Synergism; HIV Infections; Humans; No-Observed-Adverse-Effect Level; Reverse Transcriptase Inhibitors; Safety

Abacavir (Ziagen), a nucleoside analog used in combination therapy, can cause a hypersensitivity reaction in as many as five percent of patients. When this reaction occurs, the drug must be stopped immediately and never restarted. The hypersensitivity can cause fever, rash, gastrointestinal symptoms, fatigue, and life-threatening hypotension. The reaction generally occurs in the first six weeks of treatment. The risk of hypersensitivity has long been recognized, but it is often misdiagnosed as a respiratory ailment. Glaxo Wellcome sent out a letter in January 2000 to warn health care providers about the reaction and how to diagnose it; the full text of that letter is included. The manufacturer has also relabeled the drug with stronger warnings; the Web site address is provided for further information on the change in labeling.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans

Topics: Dideoxynucleosides; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors

Topics: Dideoxynucleosides; Drug Approval; Drug Costs; HIV Infections; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Internet; Practice Guidelines as Topic; Reverse Transcriptase Inhibitors

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Child; Cyclopropanes; Developed Countries; Developing Countries; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors

Topics: Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

Topics: Anaphylaxis; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Fatal Outcome; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors

Topics: Adult; Agranulocytosis; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; IMP Dehydrogenase; Mycophenolic Acid; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Approval; Drug Hypersensitivity; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Mutation; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Long-term management of HIV shows that combination therapy can achieve viral loads of under 50 copies, sustainable for 3 years or more. Highly affective antiretroviral therapy (HAART) is the most effective prevention against opportunistic infections due to its ability to stimulate the immune system. Some statistics show as much as an 82 percent decline in opportunistic infections in patients on HAART. Combination therapy does not work equally well for everyone, largely due to side effects and cross resistance, but newer medications and regimens appear more effective and have fewer side effects. Updated information is given for several new anti-HIV drugs, including amprenavir and adefovir (Preveon, 1592U89). Results of recent clinical trials with these drugs, including their effectiveness in restoring immune system strength, are reviewed. Genotypic and phenotypic resistance testing are also discussed.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Abacavir (Ziagen), a newly approved nucleoside analog, could be one of the most potent antiretrovirals available. Most of the clinical trials on abacavir have focused on patients who have never been treated for HIV, and they have responded well to the drug. The drug is not expected to be as effective in patients who have exhausted treatment options, as was demonstrated by Glaxo study CNA2007. The most common side effect of abacavir was skin rash. Some participants also reported systemic flu-like symptoms. Abacavir shows promise in intensification therapies where a drug is added to an established regimen that is not working, and in salvage therapies where patients have few treatment options remaining.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Codon; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Mutation; Salvage Therapy; Viral Load; Virus Replication

The Food and Drug Administration (FDA) announced accelerated approval of Glaxo-Wellcome's abacavir (Ziagen, 1592) in combination with other antiretrovirals. Abacavir is in the same nucleoside analog class as AZT, but abacavir has stronger effects against HIV. Use of the drug requires caution, because it can cause a serious hypersensitivity or allergic reaction in 5 percent of patients. If abacavir is stopped and restarted, the hypersensitivity can be more fatal. Little is known about long-term use of the drug or its effects when in combination with other anti-HIV medications other than AZT plus 3TC.

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Approval; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans; United States Food and Drug Administration

HIV/AIDS was the subject of some of the presentations at the annual meeting of the Infectious Diseases Society of America (ISDA). The most significant presentation was by Dr. Anthony Fauci, who described the possibility of using IL-2 to purge latently-infected CD4 cells. Other presentations covered treatment of primary HIV infection, updates on developments of nucleoside inhibitors, an efavirenz (EFV) update, PCP prophylaxis, care delivery options, and co-infection with tuberculosis.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Colorado; Cyclopropanes; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Interleukin-2; Oxazines; Pneumonia, Pneumocystis; Practice Patterns, Physicians'; Reverse Transcriptase Inhibitors; Tuberculosis; United States

More antiretroviral drugs are becoming available, increasing potential treatment regimens but also increasing the complexity of HIV treatment. The 4 newest of the 15 available antiretroviral agents are described: efavirenz (Sustiva, EFV), abacavir (Ziagen, ABC), adefovir (Preveon, ADV), and amprenavir (Agenerase, APV). Information on dosing, side effects, and interactions with other drugs is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Sulfonamides

Research presented at the 6th Conference on Retroviruses and Opportunistic Infections suggests that highly active antiretroviral therapy (HAART) does not have to include protease inhibitors to be effective. Other drug combinations should achieve positive results; the potency of the drug combination is the most important. Two 48-week trials, one including the non-nucleoside reverse transcriptase inhibitor Sustiva (efavirenz) and the other consisting of all nucleoside reverse transcriptase inhibitors, have shown that a protease-sparing regimen can be just as potent and durable. These regimens are even more attractive because of lower prices and the lack of side effects associated with protease inhibitors. The results of these two studies will give clinicians more HAART options.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Oxazines; Patient Compliance; Pregnancy; Reverse Transcriptase Inhibitors; Zidovudine

The 6th Conference on Retroviruses and Opportunistic Infections included some significant information on initial HIV therapy. Data from the Dupont 006 efavirenz (EFV)/AZT/3TC trial are provided in a table and demonstrate the excellent potency and durability of efavirenz. The Atlantic Trial compares three 3-drug regimens. Twenty-four week results are presented, including evidence that median increases in CD4 counts are similar between the groups. In addition, researchers from the conference presented 24-week data from two open trials of ABT 378 in combination with Ritonavir. This drug shows great tolerability and potency. Details from each trial are discussed.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chicago; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors

A number of important studies at the 6th Conference on Retroviruses and Opportunistic Infections addressed using antiretroviral therapy in treatment-experienced patients. The growing availability of resistance assays and the expanding list of antiretroviral drugs make therapy both more complex and more effective. Results are presented from studies with nucleoside-experienced patients and protease inhibitor-experienced patients. The role of intensification is discussed and three definitions of that approach are explained. The use of resistance testing in guiding and modifying therapy is also discussed.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chicago; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Treatment Failure

Ribavirin (Rebetol) is Schering Corporation's newly approved drug. It is used in combination with interferon for treatment of chronic hepatitis C in patients whose compensated liver disease has not been treated or who have relapsed after interferon monotherapy. Results of clinical trials are summarized, and dosing options and side effects are detailed. Similar information is provided for abacavir (Ziagen), Glaxo-Wellcome's new nucleoside analog reverse transcriptase inhibitor (NRTI) that is used in combination therapy to treat HIV.

Topics: Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Resistance, Microbial; Hepatitis C; HIV Infections; Humans; Ribavirin

Abacavir sulfate (Ziagen) received accelerated approval for treatment of HIV infection from the Food and Drug Administration (FDA). It is the fifteenth approved anti-HIV drug. Abacavir, manufactured by Glaxo Wellcome, is currently the most powerful of the nucleoside analogue reverse transcriptase inhibitors (NRTIs). Side effects include nausea, vomiting, fatigue, headache, and diarrhea. A serious hypersensitivity reaction occurs in approximately 5 percent of patients taking the drug. Patients who experience this reaction can never take the drug again, because subsequent reactions can be fatal. Drug interactions may be minimal, as abacavir is not metabolized by the same enzymes that metabolize several other anti-retrovirals. Resistance is also discussed and clinical data from studies are presented.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Federal HIV treatment guidelines will soon include recommendations about selecting salvage therapy and will provide advice on understanding the increasingly complex science of cross-resistance and HIV mutations. The increasing number of HIV drugs makes selecting a salvage therapy more difficult. The guidelines will upgrade the nucleoside analog reverse transcriptase inhibitor abacavir (Ziagen) to an alternative treatment. In addition, hypersensitivity to abacavir and the differences in progression of HIV disease between women and men are described.

Topics: Adolescent; Adult; Anti-HIV Agents; Dideoxynucleosides; Disease Progression; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Practice Guidelines as Topic; Salvage Therapy; United States

Available HIV drugs fall into three classes: nucleosides (nukes), non-nukes and protease inhibitors (PIs). Cross-resistance can occur, making all the drugs in a particular class ineffective for an individual. Therefore, doctors are choosing to use the fewest drugs possible for early treatment, saving other drugs for later therapy. Short-term results of triple therapy with three nukes (AZT, 3TC, and ABC (abacavir)) have been promising, especially among patients with little prior exposure to antiretroviral drugs. Thus some doctors are using triple nuke therapy in recently infected patients, and others with high CD4+ counts and low viral loads.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; France; HIV Infections; Humans; Lamivudine; Zidovudine

The wholesale pricing of abacavir (Ziagen), a nucleoside analogue reverse transcriptase inhibitor, was proposed at $9.70 per day. A 15 percent discount will be given through State AIDS Drug Assistance Programs (ADAPs). Communication between pharmaceutical companies and representatives of the HIV community is important to ensure that costs remain affordable.

Topics: Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans

The Food and Drug Administration (FDA) approved Glaxo Wellcome's nucleoside analog, abacavir (Ziagen, formerly 1592), for combination anti-HIV regimens for adults and children. In an early trial, abacavir was effective in suppressing HIV replication in combination with other antiretroviral drugs. Abacavir is generally well-tolerated, with minimal side effects. People who experience severe side effects within six weeks after starting abacavir should contact their doctor immediately. If medication is stopped due to severe hypersensitivity, it should not be restarted because it could result in a life-threatening reaction.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Laboratory studies indicate that mycophenylate (CellCept) may increase the anti-HIV activity of abacavir (Ziagen). Mycophenylate suppresses the production of guanosine, which is critical to the replication of HIV. Although the combination of mycophenylate and abacavir has been shown to have a similar effect to that of the combination of Hydroxyurea and ddI, it may be more powerful and less toxic. These results are preliminary and must be confirmed by human studies, which are currently under way.

Topics: Dideoxynucleosides; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prodrugs; Reverse Transcriptase Inhibitors

To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients.. A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance.. The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance.. Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir.

Topics: Anti-HIV Agents; Cohort Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Methionine; Point Mutation; Reverse Transcriptase Inhibitors; Stavudine; Valine; Zalcitabine; Zidovudine

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Topics: Adult; Aged; Anti-HIV Agents; Carbamates; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Ki-67 Antigen; Lymph Nodes; Male; Middle Aged; Reverse Transcriptase Inhibitors; Sulfonamides

To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs.. Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study.. Participants with > or = 10 000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers.. The elimination rate constants for HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens.. With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

Topics: Adult; Anti-HIV Agents; Data Interpretation, Statistical; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Virus Replication; Zidovudine

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Dideoxynucleosides; Dizziness; Drug Therapy, Combination; Headache; HIV Infections; Humans; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Antipsychotic Agents; Blood-Brain Barrier; Central Nervous System; Cytochrome P-450 Enzyme System; Dementia; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Mental Disorders; Nevirapine; Reverse Transcriptase Inhibitors

The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in the ex vivo human placental model.. The ex vivo human placental model used C14 antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by high pressure liquid chromatography.. The clearance index of abacavir was 0.47 +/- 0.19 and 0.50 +/- 0.07 at peak and trough concentrations, respectively. The clearance index of amprenavir was 0.38 +/- 0.09 and 0.14 +/- 0.08 at peak and trough concentrations, respectively. There was no unusual accumulation of either drug in the media or tissue when the perfusion system was closed.. Abacavir is the first nucleoside compound studied in the perfusion system with a high clearance index. The transfer of the protease inhibitor amprenavir had a clearance index 2.75 times greater than the clearance index of ritonavir at peak concentration determined in a previous study. At trough concentration the clearance index was much less than at the peak concentration. A similar result was found with ritonavir.

Topics: Carbamates; Dideoxynucleosides; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Sulfonamides

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Industry; Health Services Accessibility; HIV Infections; Humans; Patient Selection

In response to pressure from AIDS groups, Glaxo Wellcome agreed to make its nucleoside analog abacavir (1592) available to more people. The drug will be given to people who are not otherwise able to construct an effective treatment option. The program should be in place by the end of the first quarter of 1998. A telephone number is provided for further information.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drugs, Investigational; HIV Infections; Humans

Some of the latest developments in HIV treatment are described and contact information is given for people seeking further information on the topic. Clinical studies and preliminary results for interleukin-2 (IL-2), 1592U89 (abacavir), DMP-266 (efavirenz or Sustiva), and 141W94 (VX-94, Vertex) are described. Pharmaceutical companies are expected to continue developing new HIV drugs, including those in new drug classes, that will be more convenient, palatable, and less prone to resistance.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-2; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Glaxo Wellcome has expanded its access program for its experimental drug abacavir (Ziagen, formerly known as 1592). The program already includes 1900 patients since its start last summer and the newly expanded program is less restrictive. Patients over 13 years of age who have already failed standard treatments are eligible. These patients must take Ziagen as part of a combination antiretroviral treatment including at least one other antiretroviral the patient has never taken before. Pregnant or nursing women, and patients with medical conditions who cannot use the drug safely are excluded. Children under 13 years old may participate in a pediatric program. Presently it is not clear who would benefit from taking abacavir. An estimated three percent of patients taking Ziagen experienced hypersensitivity reaction, characterized by a fever in conjunction with nausea, malaise and possibly a rash. If hypersensitivity occurs, the patient must discontinue use indefinitely; symptoms will disappear within one to two days of termination. More information is available from the Abacavir Coordinating Center.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans

Glaxo Wellcome is offering an expanded access program for abacavir (Ziagen, formerly 1592) to HIV-positive patients who are not benefiting from their current combination therapy. In a dramatic departure from the usual entry criteria, the abacavir eligibility criteria require no specific CD4 cell count or viral load. To qualify, volunteers must be on a failing regimen, unable to tolerate standard therapies, and a physician must verify that another drug combination would not be viable. Patients are urged to switch to a regimen of at least two new drugs based on U.S. government treatment guidelines. Similar programs are available for the anti-HIV drugs efavirenz (Sustiva) and adefovir dipivoxil (Preveon). People using abacavir, a nucleoside analog, may experience side effects such as headache, nausea, and vomiting. If a hypersensitivity reaction develops, patients must stop the treatment. Taking the drug after experiencing an adverse reaction can be life threatening.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drugs, Investigational; Health Services Accessibility; HIV Infections; Humans; United States

The 5th Conference on Retroviruses and Opportunistic Infections included 837 abstracts and oral presentations on clinical and basic science aspects of HIV. A major theme of the conference was the effectiveness of newer anti-HIV therapies, and there were many sessions dealing with combination treatments, including six-drug treatments. Results of studies with several drugs, including abacavir, efavirenz, amprenavir, PMPA Prodrug, adefovir dipivoxil, hydroxyurea, and protease inhibitors in several combinations are summarized. Treatments for opportunistic infections, including MAC, CMV retinitis, herpesvirus, and tuberculosis, are also presented.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antiviral Agents; Benzoxazines; Carbamates; Chicago; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Glaxo Wellcome has expanded its access program for the nucleoside analog abacavir (Ziagen). Currently there are no CD4 count or viral load requirements and the program is open to patients over age 13 who have failed standard treatments. Pregnant and breastfeeding women are excluded from the study. Patients must take Ziagen with at least one other new anti-HIV drug. In a previous trial, approximately three percent of people taking abacavir developed a severe hypersensitivity reaction that forced interruption of treatment. After suspension of treatment, initial symptoms subside, however, the syndrome could reappear in life-threatening proportions should treatment be resumed. Physicians have a limited window to enroll patients in the expanded program because abacavir is anticipated to get clearance from the Food and Drug Administration (FDA) in the fall.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Therapy, Combination; Health Services Accessibility; HIV Infections; Humans

Three experimental drugs, efavirenz (Sustiva), abacavir (Ziagen), and adefovir dipivoxil (Preveon), are now available through expanded access programs for people who are running out of treatment options. The dosage, drug interactions, side effects, and expanded access requirements are outlined. Contact information for enrolling in these programs is provided.

Topics: Adenine; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; Humans; Oxazines; Reverse Transcriptase Inhibitors; Salvage Therapy

A Glaxo-Wellcome study of anti-HIV-drug-naive patients taking amprenavir at 1200 mg and abacavir at 300 mg twice daily reveals viral load drops to below 500 copies. Another study involving abacavir at 300 mg, amprenavir at 1200 mg, AZT at 300 mg, and 3TC at 150 mg, all taken twice daily was conducted with recently infected patients and chronically infected patients. Viral load drops and rises in CD4+ cell counts were reported in both groups after 20 weeks. A rash associated with abacavir tends to occur in about 5 percent of the patients tested. Fatigue, nausea, vomiting, and fever are also possible side effects.

Topics: Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Sulfonamides; Viral Load; Zidovudine

An overview is presented on the following three anti-HIV drugs: abacavir, efavirenz, and preveon. All three drugs are currently available through expanded access programs, are dosed either once or twice daily, and can be taken with or without food. Patients who have never used anti-HIV therapies can benefit most from these new drugs. Patients who are highly experienced with anti-HIV therapy and in search of new regimens may find little help from these new entrants. Drug manufacturer's contact information is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiviral Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Approval; Drug Therapy, Combination; HIV Infections; Humans; Oxazines; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

There are a number of new developments in the fight against the HIV epidemic. New drugs are being developed, results are being reported from a number of clinical trials, and there are some new strategies in disease management. Currently, there are eleven approved medications for HIV. Several new drugs or studies are highlighted: adefovir dipivoxil (preveon), which is now available under an expanded access program; abacavir (GW1592U89, efavirenz), which shows promise as an antiretroviral ten times more effective than AZT; amprenavir (141W94, VX-478), a new protease inhibitor nearing the end of clinical trials; Fortovase (soft-gel Saquinavir), which is proving much more effective than its earlier formulation; and Hydroxyurea (HU), a long-approved anti-cancer drug which enhances the effectiveness of other HIV medications. Several drugs under development are discussed, such as ABT-378, which show great promise in the treatment arsenal.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Carbamates; Decision Making; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Patient Compliance; Saquinavir; Sulfonamides

Abacavir (ABC), an experimental nucleoside reverse transcriptase inhibitor created by Glaxo Wellcome, appears as effective in combination therapy as protease inhibitors, when ABC is combined with Combivir. Combivir is a two-drugs-in-one combination comprised of AZT and 3TC. ABC was developed as an investigational treatment for HIV and is currently in Phase III trials for adults and children. This is the first time that three drugs in the same class have effectively reduced the viral load of treatment-naive patients to levels usually only seen with protease inhibitors. Trial results are nearly identical to those where AZT, 3TC, and a protease inhibitor have been combined. ABC can potentially change the way treatment is initiated because it involves a simple regimen. Due to its potency, fewer pills are necessary. There are also very few side effects or serious drug interactions associated with ABC.

Topics: Adipose Tissue; Anti-HIV Agents; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Patient Compliance; Patient Education as Topic; RNA, Viral; Viral Load

Since many new anti-HIV drugs are variations of currently available drugs, they may be more effective for people who are beginning treatment. One study shows favorable results when using efavirenz in triple combination therapy; however, it is recommended that this therapy be reserved for people who are treatment-naive and symptom-free. It is still unclear if all non-nucleoside RT inhibitors (NNRTIs) are as potent as efavirenz and whether the long-term potential for them is as promising as standard combinations. Researchers caution against pairing an NNRTI with a protease inhibitor in the event that resistance to the combination develops. That resistance may eliminate the option of using any other protease inhibitor or NNRTI in future therapies. Conversely, abacavir, an NARTI, has been effective in combination with many protease inhibitors. Amprenavir shows good antiviral activity; although studies show that it may not be successful as a salvage therapy with protease inhibitors. Nucleotide analogue reverse transcriptase inhibitors, such as adefovir and bis-poc PMPA, showed moderate anti-HIV potency. A study evaluating FTC alone showed a good reduction in viral load. FTC also fights hepatitis B and requires only one dose daily. Information is included about expanded access programs for abacavir, adefovir, and efavirenz.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides; United States; Zidovudine

Treatment activists are circulating a letter opposing drug-pricing strategies for abacavir (Ziagen) and efavirenz (Sustiva). The groups are concerned that these drugs will be priced significantly higher than other nucleoside analogs and non-nucleoside reverse transcriptase inhibitors. The statement notes that higher survival rates should insure drug manufacturers of a steady supply of patients, allowing them to lower prices and still make a profit. Both drugs are appropriate for treatment-naive and treatment-experienced patients, making the potential market for them large. The letter is sponsored by the Fair Price Working Group, which includes members from Project Inform, ACT UP/New York, the San Francisco AIDS Foundation, GMHC Treatment Issues, Foundation for AIDS and Immune Research, and AIDS Treatment News. Contact information is included.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Economics, Pharmaceutical; HIV Infections; Humans; Oxazines; Reverse Transcriptase Inhibitors; United States

To augment the limited antiviral treatments available for children, new therapies to treat children are being investigated. On recommendation from Federal guidelines, many treatment regimens approved for adults are being prescribed for children, but these have little information available about dosing and long-term effects. Ritonavir in different combinations and dose levels has shown good short-term results, and it is believed that the long-term outcomes will mirror the adult outcomes. The Pediatric AIDS Clinical Trials Group study 338 indicated that the three- drug combinations used had a similar impact on viral load when compared to the adult studies. An additional study of Ritonavir, given as a salvage therapy to children with high viral loads, illustrates that pediatric trials should use the experiences learned from adult trials to formulate beneficial regimens. Descriptions of studies for children utilizing Nelfinavir, Saquinavir, and abacavir describe the triple drug combinations that were most successful, the side effects that were experienced, and the need for liquid formulations of the drugs for easier administration. Critical issues that need to be addressed are: adherence to treatment, modifications of side effects, toxicity, and appropriate dosing. A summary of current Federal guidelines for treating children and adolescents with HIV is included.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Nelfinavir; Practice Guidelines as Topic; Ritonavir; Saquinavir; Viral Load

Highly active antiretroviral therapies (HAART) that do not incorporate a protease inhibitor (PI) have received much attention in attempts to find effective treatment alternatives. HAART without PIs can extend the future options of some patients, to allow switching to a PI therapy later in treatment, or to avoid unpleasant side effects reported with some PIs. A study of combination therapy employing efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) showed encouraging results, as did a similar study employing abacavir. However, researchers are cautious about the ability of these drugs to sustain high antiviral activity over a long-term period. As a potent alternative to HAART, NNRTI's offer easier dosing and appear to have similar results, albeit in the short-term. Studies of Hydroxyurea have reported a positive antiviral response. However, one study indicated that the positive response came with significant side effects. The use of anti-HIV therapy in pregnant women and their newborns is the subject of another study, that assessed the safety of treatment and the possible side effects. Comparisons of protease inhibitor-containing regimens are also reviewed. Alternative two-drug combinations of Indinavir and Ritonavir, and abacavir and amprenavir are explored.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Viral Load

Salvage therapies are treatments that are implemented for people who have been unable to suppress viral loads below the limit of quantification using one or more protease inhibitor- containing regimens. Results of a small study showed that 20 people raised their antiviral activity by adding Nevirapine, a non-nucleoside reverse transcriptase inhibitor, to triple combination therapy. Results of the 20-week study are presented. The effects of switching to a regimen that introduced two potent antiviral drugs were shown to be more significant than changing to a regimen that included two protease inhibitors. Greater decreases in HIV levels were seen in participants who, prior to the start of the study, showed lower phenotypic resistance to the drugs that were going to be used in the study.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Nelfinavir; Nevirapine; Reverse Transcriptase Inhibitors; Salvage Therapy; Saquinavir; Viral Load

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

The FDA Antiviral Advisory Committee has recommended the approval of abacavir (Ziagen), a nucleoside analog that is produced by Glaxo Wellcome. Abacavir will be the thirteenth HIV drug to win approval. Glaxo applied under the FDA's accelerated approval statutes, which allow for conditional approval of lifesaving drugs. This approval is based on preliminary data, and can only be applied for when no other feasible treatment alternative exists. Results from the early tests are presented, along with toxicity data. Abacavir is a relatively safe drug, however, approximately 3 percent of people taking abacavir, have suffered from severe allergic reactions. Pricing information is included.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Approval; Drug Costs; Drug Therapy, Combination; HIV Infections; Humans; United States; United States Food and Drug Administration

An advisory committee of the Food and Drug Administration (FDA) has recommended accelerated approval for abacavir (ABC, Ziagen). The approval decision was not unanimous due to concerns of drug toxicity. Three percent of those taking the drug have developed severe allergic reactions, and at least eight people have died of complications related to the allergic reaction. Abacavir works by attacking the viral enzyme reverse transcriptase (RT), and it is related to other drugs such as AZT, 3TC, d4T, ddI, and ddC. Abacavir should be taken twice daily, in combination with other anti-HIV medications.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Approval; Drug Therapy, Combination; HIV Infections; United States; United States Food and Drug Administration

The FDA Antiviral Drug Products Advisory Committee recommended accelerated approval for abacavir. The most important trial compared abacavir plus AZT and 3TC versus Indinavir plus the same two drugs. The results of the two combinations are similar; however, the trial is still blinded, so it is not known which group is receiving which medications. Transcripts and further information are available on the FDA web site.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Approval; Drug Therapy, Combination; HIV Infections; Humans; United States; United States Food and Drug Administration

Some physicians are beginning to prescribe potent drug cocktails that do not include protease inhibitors. This is a departure from the standard treatment that has included protease inhibitors since their introduction in recent years. Protease inhibitors remain among the most effective and important treatments developed, but there are significant problems, including cross-resistance and patient intolerance. Also, protease inhibitors are associated with serious side effects such as lipodystrophy. Protease-sparing regimens such as abacavir/AZT/3TC and drug combinations that include efavirenz appear to be as effective as protease-inhibitor containing regimens. Results of new treatment approaches are summarized.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Lamivudine; Lipodystrophy; Oxazines; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine

DuPont Pharmaceuticals and Glaxo Wellcome began marketing two new drugs, and the pricing of the drugs started a controversy. DuPont's efavirenz (Sustiva) was priced 60 percent higher than any other nonnucleoside reverse transcriptase inhibitor (NNRTI), with an annual retail price close to $5,000. In response, an ad hoc coalition called the Fair Price Working Group circulated a consensus statement demanding that the drug be priced like other drugs in that category. DuPont refused to reconsider, citing potency, once-daily dosing, and development costs. Several of the largest AIDS Drug Assistance Programs (ADAPs) also refused to add efavirenz to their formularies even though Dupont offered ADAPs a 5 percent rebate on the drug. Glaxo Wellcome learned from this dispute and priced its nucleoside analog abacavir at a level that ADAPs could afford, even though it is at the high end for its class of drugs. The coalition commended Glaxo for fairness in its pricing decision. Agouron and Bristol-Myers Squibb have also been criticized for repeatedly raising prices on their drugs. A continuing dialog, prior to price setting, will lead to greater understanding of a company's costs and may improve a company's reputation.

Topics: Alkynes; Anti-HIV Agents; Antiviral Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Packaging; Drug Therapy, Combination; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Interferon alpha-2; Interferon-alpha; Oxazines; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin; United States

Glaxo Wellcome's announced price for Ziagen (abacavir) was less than many expected. The drug will cost wholesalers $3,540 per year, which is significantly less than the price that DuPont Pharma set for Sustiva (efavirenz). Discounts on Ziagen will be provided to AIDS Drug Assistance Programs (ADAPs). DuPont has also made modest price concessions for its drug, promising not to raise the price for at least 3 years and giving ADAPs a 5 percent rebate. Ziagen has not yet received marketing approval.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; Humans; Oxazines; Reverse Transcriptase Inhibitors; United States

Glaxo Wellcome's new drug, Ziagen (abacavir), was recently recommended to the Food and Drug Administration (FDA) for accelerated approval. Ziagen appears to have significant antiviral activity, and its dosage is one pill twice a day. Data from various studies of the drug show it to be effective in previously untreated patients. Glaxo Wellcome also filed a New Drug Application for Agenerase (amprenavir), a new protease inhibitor. Preliminary data presented at ICAAC showed it to be effective in multi-drug combinations. Agenerase is taken twice daily without any food or water restrictions and is available through an expanded access program. Contact information is provided.

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Sulfonamides

Abacavir (Ziagen), a nucleoside analogue, is expected to be approved by the FDA for treatment of HIV in adults and children, and be available by the end of the year. Studies indicate abacavir is the most potent of the six approved nucleoside analogues in people who are treatment-naive. Information on dosing and side effects is given. A serious hypersensitivity reaction, occurring in about 3 percent of people, usually resolves within one to two days after discontinuing the drug. Abacavir should not be used again in these people, however, as the subsequent reaction can be fatal.

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Approval; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; Humans; United States Food and Drug Administration

Amprenavir, abacavir, and adefovir are available at no cost during their final approval phase by the FDA. Eligibility requirements for receiving the drugs and contact information are provided.

Topics: Adenine; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Sulfonamides

New anti-HIV drugs that are expected to become available in the future are discussed. The potent protease inhibitor amprenavir (Agenerase) is expected to be available in pharmacies by early 1999. Results of a study of treatment-naive, HIV-positive people showed that those taking amprenavir as part of a three-drug combination therapy, with AZT and 3TC, had better viral reduction than those using AZT and 3TC alone. In a French study of the non-nucleoside reverse transcriptase inhibitor Nevirapine, and a similar study of Delavirdine, a majority of participants had HIV RNA levels below the limit of detection. Further comparative studies are needed between Nevirapine, Delavirdine and the more costly, highly publicized competitor, efavirenz. Several studies of regimens that include protease inhibitors compare dosing twice daily to three times a day. A Canadian study describes salvage therapies, for people who have failed previous treatment with protease inhibitors, that can include up to nine drugs. Because there is a shortage in the development of new types of HIV drugs, people are encouraged to carefully consider when to begin treatment and what medical options are available.

Topics: Anti-HIV Agents; Carbamates; Delavirdine; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides

Highlights from the 38th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) included a tribute to Jonathan Mann and Mary-Lou Clements Mann and a review of HIV drugs recently approved and currently in development. Information is provided about efavirenz, abacavir, amprenavir, and adefovir, including the classification, dosing, and side effects of these drugs. Data from recent trials of these new drugs can be used to determine the best course of treatment for treatment-naive and treatment-experienced patients. New nucleoside reverse transcriptase inhibitors reviewed are lodenosine (FDDA), FTC, BCH-10652, and DAPD. Non-nucleoside reverse transcriptase inhibitors described include MKC 442 and PNU 142721. Other drugs under development include bis(POC) PMPA, a nucleotide RTI, and several protease inhibitors. T-20, an enzyme that interferes with envelope fusion, is also in development.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

A chart provides profile information on Agenerase (amprenavir), Ziagen (abacavir) and Preveon (adefovir). Basic questions about drug type, storage, dosing, and benefits for people with or without previous antiviral experience are answered. Drug interactions, side effects, and pediatric use are also covered for these three drugs, which are only accessible through expanded access programs. Contact information is provided.

Topics: Adenine; Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Child; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Male; Pregnancy; Sulfonamides

Glaxo Wellcome reports that 2-3 percent of patients in their clinical trial of the nucleoside analog abacavir (1592) have a hypersensitivity to the drug. Patients experience fever, severe nausea, and a generalized rash, usually occurring an average of 11 days after treatment begins. Symptoms subside when the drug is discontinued and return immediately when the drug is restarted.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

Agouron Pharmaceuticals trial results suggest additional treatment options for people taking or considering taking Viracept in combination with other anti-HIV drugs. The clinical test results with Viracept and other drugs are presented. Viracept was tested for safety and efficacy with Fortovase (saquinavir soft gel), Norvir (ritonavir), Crixivan (indinavir), 1592 (abacavir), and non-nucleoside reverse transcriptase inhibitors.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors

Presentations at the Fifth Conference on Retroviruses and Opportunistic Infections focused on new and novel HIV treatments. Four new agents in advanced testing are described: abacavir (1592), efavirenz (DMP-266), adefovir dipivoxil (bis-POM PMEA), and amprenavir (141W94). Other new drugs are being developed; however, the drugs are not as far along in the testing and approval process. The new drugs include integrase inhibitors, zinc finger inhibitors, cyclams and bycyclams, fusion inhibitors, and CKR-5 gene therapy. A summary of each drug is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; Genetic Therapy; Heterocyclic Compounds; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Oxazines; Receptors, Chemokine; Reverse Transcriptase Inhibitors; Sulfonamides; Zinc Fingers

Ron Baker of the San Francisco AIDS Foundation discusses the presentation highlights at the Fifth Conference on Retroviruses and Opportunistic Infections with Dr. Harvey Bartnoff of the AIDS Virus Education and Research Institute, Dr. Steven Deeks of the University of California, and Dr. Stephan Follansbee of the Institute for HIV Research and Treatment. The panel discusses trends in testing and treatment, drug interactions, and studies of several therapies, including amprenavir, hydroxyurea, and adefovir. Dr. Mellors described study results of abacavir used in combination with protease inhibitors. The panel of doctors emphasize that abacavir is very effective; however, it needs to be used carefully in case a reaction occurs. If the drug is restarted, the allergic reaction may result in death.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Furans; Genetic Techniques; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

The carbocyclic nucleoside 1592U89 is a selective inhibitor of the human immunodeficiency virus (HIV), targeting the reverse transcriptase (RT). In vitro selection studies were undertaken to generate resistant variants with both HIV type 1 (HIV-1) wild-type strain HIV-1(HXB2) and 3'-azido-3'-deoxythymidine (AZT)-resistant strain HIV-1(RTMC). At least two or three mutations in RT were required to produce a 10-fold reduction in susceptibility. The first RT mutation selected was at codon 184, methionine (M) to valine (V), for HIV-1(HXB2) and HIV-1(RTMC), conferring two- and fivefold resistance, respectively. Two additional mutations were selected with HIV-1(HXB2), either leucine (L) 74 to V and lysine (K) 65 to arginine (R) (first-passage series) or L74 to V and tyrosine (Y) 115 to phenylalanine (F) (second-passage series). Cloned variants, obtained from the 1592U89 selection, were either double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Molecular clones were constructed with single, double, and triple combinations of these mutations for resistance analysis with different RT inhibitors. Each individual mutation conferred only low-level resistance (two- to fourfold) to 1592U89 in the HXB2 background. Double mutants containing the 184V mutation and triple mutants showed slightly greater levels of resistance to 1592U89 (7- to 11-fold). Some of the 1592U89-resistant variants were cross-resistant with 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and (-)-2'-deoxy-3'-thiacytidine, but none were resistant to 2',3'-didehydro-3'-deoxythymidine or AZT.

Topics: Anti-HIV Agents; Cells, Cultured; Codon; Dideoxynucleosides; Drug Resistance, Microbial; Genetic Linkage; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation

A preliminary report on Glaxo-Wellcome's nucleoside analogue 1592 indicates that the drug is a powerful antiretroviral; however, cross-resistance has occurred in patients treated previously with AZT/3TC. The drug may be most effective in 3TC-naive patients. The dosage is 300 mg taken orally twice daily; however, optimal use of 1592 remains unknown. A telephone number is provided for further information about 1592.

Topics: Administration, Oral; Anti-HIV Agents; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors

Gilead Sciences will offer an expanded access program for its anti-HIV agent, adefovir (Preveon). Prospective enrollees must have CD4 counts less than 50, a viral load of over 30,000 copies/ml by PCR within the past 2 months, and failed at least two nucleoside analogs and one protease inhibitor. Because adefovir has extremely modest activity, it can only function as an adjunct to other potent drug combinations. There is concern that the eligibility requirements will be problematic. DuPont Merck's non-nucleoside reverse transcriptase inhibitor Sustiva is undergoing participant registration for its expanded access program. Participants must have CD4 counts less than 50 but may have any viral load level. Glaxo's expanded access program for abacavir (1592U89) is an open-label trial with eligibility being CD4 counts less than 100. Glaxo has also opened an expanded access program for patients with moderate to severe AIDS dementia.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Viral Load

Community groups called off a boycott of Glaxo Wellcome products when the company was viewed as developing a more constructive dialogue and cooperative spirit in planning its 1592 expanded access program. Community representatives made several proposed changes to the 1998 program including no arbitrary limitation on study size, creation of a broader expanded access program, and greater flexibility in drug availability. Current delays in access to 1592 and other experimental drugs have been due to local institutional review boards (IRBs) prioritizing vital access programs behind more routine research projects. Glaxo's national IRB system has met with resistance from some hospitals who wish to use their own IRBs. However, community representatives remain hopeful that Glaxo will address access for all patients who need 1592 for the 1998 program.

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; HIV Infections; Humans; Patient Selection; Professional Staff Committees; Reverse Transcriptase Inhibitors

A phase II multicenter trial is underway to test the effectiveness of three new antiretrovirals in patients who are failing combination protease inhibitor therapy. The study, organized by Glaxo Wellcome, is testing the effectiveness of a combination of 1592, 141W94, and efavirenz (Sustiva or DMP-266). Volunteers must be at least 13 years old, with viral loads over 500 following protease inhibitor therapy. Other criteria include no AIDS-defining opportunistic infections or malignancies except Kaposi's sarcoma. Each of the drugs has side effects associated with it, and rash has been the most common reason for each drug to be discontinued.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Clinical Trials, Phase II as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Male; Multicenter Studies as Topic; Oxazines; Patient Selection; Reverse Transcriptase Inhibitors; Sulfonamides; Treatment Failure

Caution is advised when using the experimental antiretroviral abacavir (1592U89) in the event of a systemic hypersensitivity reaction because continued use may be life-threatening. Glaxo is planning research to determine the cause of the hypersensitivity and is educating physicians, researchers, and volunteers in clinical trials about abacavir hypersensitivity. The Food and Drug Administration (FDA) has been informed as well.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Abacavir (1592U89), once thought to be a promising new nucleoside analog, has some troubling side effects and limitations. It is being made available on a compassionate use program both for children and for adults who meet specific criteria and are failing standard therapy. Little information is available on abacavir from early studies. Side effects have been observed in studies with only a small number of volunteers, and include increased fatigue, changes in liver function tests, and gastrointestinal distress. The drug does not enter cerebrospinal fluid, in spite of early encouraging tests that showed that it might be effective in crossing the blood-brain barrier. In addition, in patients who have developed resistance to other nucleoside analogs, the use of abacavir adds very little anti-HIV effect. Patients are cautioned to wait for new drugs to be developed, unless they are in an emergency situation.

Topics: Adolescent; Adult; Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Therapy, Combination; Female; Health Services Accessibility; HIV Infections; Humans; Infant; Male